Catalytic compositions and methods for asymmetric aldol reactions

ABSTRACT

Methods and compositions are provided for the direct catalytic asymmetric aldol reaction of aldehydes with donor molecules selected from ketones and nitroalkyl compounds. The reactions employ as catalyst a Group 2A or Group 2B metal complex of a ligand of formula I, as defined further herein.

[0001] This application claims priority to U.S. provisional applicationserial No. 60/244,833, filed Nov. 1, 2000, which is hereby incorporatedby reference in its entirety.

[0002] This invention was made with the support of the National ScienceFoundation and the National Institutes of Health, General MedicalSciences. Accordingly, the U.S. Government may have certain rights inthis invention.

FIELD OF THE INVENTION

[0003] The present invention relates to methods and compositions for thedirect catalytic asymmetric aldol reaction of aldehydes with ketones ornitroalkyl compounds.

REFERENCES

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[0007] Carreira, E. M., in Comprehensive Asymmetric Catalysis, Jacobsen,E. N., Pfaltz, A., Yamamoto, H., Eds. (Springer, Heidelberg, 1999), vol.3, 998.

[0008] Crisp, G. T. and Turner, P. D., Tetrahedron 56:407-15 (2000).

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[0010] Heathcock, C. H., in Asymmetric Synthesis, J. D. Morrison, Ed.(Academic Press, New York, 1984), vol. 3, part B, p. 111.

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[0022] Nelson, S. G. Tetrahedron: Asymmetry 9:357 (1998).

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[0026] Ramachandran, P. V. et al., Tetrahedron Lett. 37:4911 (1996).

[0027] Sasai, H. et al., J. Am. Chem. Soc. 114:4419 (1992).

[0028] Seebach, D. et al., Liebigs Ann. Chem. 1215-1232 (1989).

[0029] Seyden-Penne, J. Chiral Auxiliaries and Ligands in AsymmetricSynthesis (Wiley, New York, 1995), Ch. 6, pp. 306-361.

[0030] Shibasaki, M. et al., Angew. Chem. Intl. Ed. Engl. 36:1236(1997).

[0031] Shibasaki, M., Sasai, H. Top. Stereochem. 22:201 (1999).

[0032] Soai, K. et al., Chem. Rev. 92:833 (1992).

[0033] Takayama, S., McGarvey, G. J., Wong, C. H. Chem. Soc. Rev. 26:407(1997).

[0034] Trost, B. M., Angew. Chem. Int. Ed. Engl. 34:259 (1995).

[0035] Van der Boom, M. E. et al., J. Am. Chem. Soc. 120:6531 (1998).

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BACKGROUND OF THE INVENTION

[0038] Few chemical reactions have reached the prominence of aldol-typereactions in the synthesis of complex molecules (Mukaiyama, 1982; Kim etal., 1991; Heathcock, 1984). The classical aldol reaction is highly atomeconomic (Trost, 1995) but suffers from poor chemo- andregioselectivity. In current practice, aldol reactions typically employa preformed enolate, enol, or equivalent; an example is the Mukaiyamareaction, which employs an enol silyl ether. These reactions generallyprovide greater selectivity, but require stoichiometric amounts of baseand/or adjunct reagents (e.g. silylating agents), thus decreasing theatom efficiency of the process. Most asymmetric versions of the aldolreaction reported to date rely upon the use of chiral auxiliaries(Seyden-Penne, 1995). Mukaiyama-type processes using asymmetriccatalysts have also been reported (Johnson et al., 2000; Carreira, 1998;Mahrwald, 1999; Groger et al., 1998; Nelson, 1998; Bach, 1994); as notedabove, these require prior stoichiometric formation of the nucleophile.Methods for direct catalytic asymmetric aldol addition, without priorstoichiometric formation of the nucleophile, are thus being sought.Processes employing both biological-type (e.g. catalytic antibodies)(Machajewski et al., 2000; Takayama et al., 1997; Hoffmann et al., 1998)and non-biological-type (Yoshikawa et al., 1999; Shibasaki et al., 1999;List et al., 2000; Notz et al., 2000; Agami et al., 1987; Nakayawa etal., 1985) catalysis have been reported. In all of these cases, however,significant excesses of the donor and/or large amounts of catalyst mustbe employed, and unbranched aldehyde substrates remain problematic. TheHenry (nitro-aldol) reaction (see e.g. Luzzio et al.) is also afundamental C—C bond forming reaction which generates stereogeniccenters. There are very few examples to date of catalytic asymmetricnitroaldol reactions. Shibasaki et al. have carried out such reactionsusing chiral heterobimetallic (rare earth-alkali metal) catalysts, andJorgensen et al. have reported the catalytic asymmetric aza-Henryreaction of silyl nitronates with imines. However, the use of silylnitronates as nucleophiles undermines the atom economy of the reaction.

SUMMARY OF THE INVENTION

[0039] The present invention includes, in one aspect, a method ofconducting an enantioselective aldol reaction between an aldehyde and adonor molecule selected from a nitroalkyl compound and a ketone bearingan α-hydrogen, the method comprising: contacting the aldehyde and donorcompound in the presence of a catalytic amount of an asymmetriccatalyst, wherein the catalyst is a complex of a Group 2A or Group 2Bmetal with a chiral ligand of formula 1:

[0040] where

[0041] R¹-R⁴ are aryl groups, which may be the same or different, eachof which is unsubstituted or substituted with one or more substituentsX, where each X is independently selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- oraryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen,

[0042] and wherein R¹ and R², or R³ and R⁴, or both of thesecombinations, may be linked at an α-carbon of each the group to form atricyclic or larger ring system;

[0043] m is an integer from 0 to 3, is preferably 1 or 3, and is morepreferably 1;

[0044] each of R⁵ and R⁶ represents one or more substituentsindependently selected from the group consisting of hydrogen and X asdefined above; and

[0045] R⁷ represents one or more substituents on the phenyl ringindependently selected from the group consisting of hydrogen, X asdefined above, and a further fused ring;

[0046] under conditions effective to produce an aldol reaction productwhich is enriched in one of the possible stereoisomeric products of suchreaction.

[0047] In selected embodiments, the Group 2A or Group 2B metal is Zn,Cd, Mg, Ca, or Ba. Preferably, the metal is zinc.

[0048] In additional embodiments, each of R¹-R⁴ is phenyl or naphthyl (αor β), unsubstituted or substituted with a group selected from X asdefined above. In preferred embodiments, each of R¹-R⁴ is phenyl ornaphthyl (α or β), unsubstituted or substituted with lower alkyl, loweralkoxy, or halogen. In additional preferred embodiments, each of R⁵ andR⁶ is hydrogen.

[0049] In further embodiments, each substituent R⁷ is selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, aryl, aralkyl,aryloxy, lower alkoxy, and halogen.

[0050] In carrying out the reaction, the donor compound and aldehyde aretypically present in a molar ratio between about 1:1 and 10:1. Theamount of catalytic complex is preferably about 2.5 to 10 mole percentrelative to moles of aldehyde. When the donor compound is anα-hydroxyketone, the molar ratio is preferably between about 1:1 and1.5:1, and the amount of catalytic complex is preferably about 2.5 to 5mole percent. When the donor compound is a nitroalkyl compound, themolar ratio is preferably about 5:1 to 10:1.

[0051] In another aspect, the invention provides a catalytic compositionconsisting of a complex of a Group 2A or Group 2B metal with a chiralligand of formula I, as defined above. The Group 2A or Group 2B metal ispreferably selected from Zn, Cd, Mg, Ca, and Ba, and is most preferablyzinc. Selected embodiments of the chiral ligand are described above.Exemplary chiral ligands include ligands 1a-1n, and preferably ligands1a, 1c-d, and 1m, as disclosed herein. The invention also encompasses acatalytic composition formed by contacting, in a suitable solvent, achiral ligand of formula I, as defined above, with a Group 2A or Group2B metal compound which is capable of generating a metal alkoxide uponreaction with an alcohol. The compound may be, for example, a dialkylmetal, dialkoxy metal, alkyl metal halide, alkyl (dialkylamino) metal,or alkyl (diarylamino) metal. The metal is preferably selected from Zn,Cd, Mg, Ca, and Ba, and is most preferably zinc. In selectedembodiments, the metal compound is a di(lower alkyl) zinc compound.Selected embodiments of the chiral ligand are described above. Inaddition, the invention provides a chiral ligand of formula I:

[0052] where

[0053] R¹-R⁴ are aryl groups, which may be the same or different, eachof which is unsubstituted or substituted with one or more substituentsX, where each X is independently selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- oraryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen,

[0054] wherein R¹ and R², or R³ and R⁴, or both of these combinations,may be linked at an α-carbon of each the group to form a tricyclic orlarger ring system;

[0055] m is an integer from 0 to 3;

[0056] each of R⁵ and R⁶ represents one or more substituentsindependently selected from the group consisting of hydrogen and X asdefined above; and

[0057] R⁷ represents one or more substituents on the phenyl ringindependently selected from the group consisting of hydrogen, X asdefined above, and a further fused ring.

[0058] In groups R¹ to R⁴, the substituents defined as group X arepreferably selected from alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy,ester, amide, sulfonamide, alkyl- or arylsulfonyl, nitro, and halogen;more preferably selected from alkyl, alkenyl, alkoxy, nitro, andhalogen; and most preferably selected from lower alkyl, lower alkoxy,and halogen. In one embodiment, each of groups R¹-R⁴ is phenyl,unsubstituted or substituted with a group selected from X above,preferably selected from lower alkyl, lower alkoxy, and halogen. Inspecific embodiments, R¹-R⁴ are identical and each is unsubstitutedphenyl, α- or β-naphthyl, or p-methoxyphenyl.

[0059] The value of m is preferably 1 or 3, and most preferably 1. R⁵and R⁶ are preferably selected from hydrogen, lower alkyl, loweralkenyl, lower alkynyl, and aryl. Each group R⁵ and R⁶ is preferablyhydrogen. In another preferred embodiment, the nitrogen heterocycles aresubstituted such that chiral centers are not formed; i.e. by having twoidentical substituents at a given position, as in a gem-dimethyl group.

[0060] The substituents defined as group X for R₇ are preferablyselected from alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy, ester,amide, sulfonamide, alkyl- or arylsulfonyl, nitro, and halogen; and morepreferably selected from alkyl, alkenyl, alkoxy, aryl, aralkyl, aryloxy,and halogen.

[0061] Representative ligands include compounds 1a-1n, shown in FIG. 1.In selected embodiments, the chiral ligand is selected from the groupconsisting of ligands 1a, 1c-d, and 1m.

[0062] These and other objects and features of the invention will becomemore fully apparent when the following detailed description of theinvention is read in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0063]FIG. 1 shows representative chiral ligands (1a-1n) of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0064] I. Definitions

[0065] The terms below have the following meanings unless indicatedotherwise.

[0066] The “chiral ligand of formula I” also encompasses ligands havingthe opposite absolute configuration to that depicted (i.e. mirror imagecompounds).

[0067] “Alkyl” refers to a fully saturated acyclic monovalent radicalcontaining carbon and hydrogen, which may be branched or a straightchain. Examples of alkyl groups are methyl, ethyl, n-butyl, t-butyl,n-heptyl, and isopropyl. “Cycloalkyl” refers to a fully saturated cyclicmonovalent radical containing carbon and hydrogen, which may be furthersubstituted with alkyl. Examples of cycloalkyl groups are cyclopropyl,methyl cyclopropyl, cyclobutyl, cyclopentyl, ethylcyclopentyl, andcyclohexyl.

[0068] “Alkenyl” refers to an acyclic monovalent radical containingcarbon and hydrogen, which may be branched or a straight chain, andwhich contains at least one carbon-carbon double bond. The alkenyl groupmay be monounsaturated or polyunsaturated. Similarly, “alkynyl” refersto such a radical having at least one carbon-carbon triple bond.

[0069] “Lower” alkyl (alkenyl, alkynyl, alkoxy, etc.) refers to a grouphaving 1 to 6 carbons, preferably 1 to 4 carbons.

[0070] “Aryl” refers to a substituted or unsubstituted monovalentaromatic radical having a single ring (e.g., benzene) or two or threecondensed rings (e.g., naphthyl; phenanthryl). Groups having a singlering (monocyclic) or two condensed rings (bicyclic) are generallypreferred, with monocyclic groups being particularly preferred. The termincludes heteroaryl groups, which are aromatic ring groups having one ormore nitrogen, oxygen, or sulfur atoms in the ring, such as furyl,pyrrole, pyridyl, and indole. Carbocyclic aryl groups are preferred forthe chiral ligands of the invention. By “substituted” is meant that oneor more ring hydrogens in the aryl group is replaced, independently,with halogen, alkyl, alkoxy, nitro, cyano, amide, tertiary amino, alkyl-or aryl sulfonyl, sulfonamide, hydroxy, or halo(lower alkyl).

[0071] “Aralkyl” refers to an alkyl, preferably lower alkyl, substituentwhich is further substituted with an aryl group; one example is a benzylgroup. Similarly, “aralkenyl” and “aralkynyl” refer to alkenyl oralkynyl substituents further substituted with an aryl group.

[0072] “Nitroalkyl compound” refers to a compound which contains anitromethyl (—CH₂NO₂) or nitromethylene (>CHNO₂) moiety and is able toform a stable carbanion on abstraction of an α-hydrogen (on the carbonadjacent the nitro group), the simplest example being nitromethane(CH₃NO₂).

[0073] II. Catalytic Compositions

[0074] In one aspect, the invention provides catalytic compositionswhich are effective to catalyze an aldol reaction between an aldehydeand a donor molecule bearing an acidic α-hydrogen, e.g. a ketone or anitroalkyl compound, to produce an aldol reaction product which isenriched in one of the possible stereoisomeric products of such areaction. In particular, the reaction is highly enantioselective.

[0075] A. Structure

[0076] The catalytic composition of the invention is a complex of aGroup 2A or Group 2B metal with a chiral ligand of formula I.

[0077] The Group 2A or Group 2B metal is preferably selected from thegroup consisting of Zn, Cd, Mg, Ca, and Ba, is more preferably Zn or Mg,and is most preferably Zn. In a series of aldol reactions conducted asdescribed herein, employing magnesium and zinc complexes, zinc complexesgenerally gave the higher enantioselectivities.

[0078] For ease of synthesis, the ligand preferably has C2 symmetry;however, this is not required.

[0079] In formula I, R¹-R⁴ are aryl groups, which may be the same ordifferent. Each of these groups is optionally substituted with one ormore substituents X, where each X is independently selected from alkyl,alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy,amide, sulfonamide, alkyl- or arylsulfonyl, hydroxy, cyano, nitro, andhalogen. In addition, any two adjacent groups (i.e. R¹ and R², R³ andR⁴, or both combinations) maybe linked via an α-carbon of each the group(i.e. a ring carbon adjacent the carbon atom linked to the carbinolcarbon) to form a tricyclic or larger ring system; e.g., a fluorene,xanthene, or dihydroanthracene ring system.

[0080] In groups R¹ to R⁴, the substituents defined as group X arepreferably selected from alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy,ester, amide, sulfonamide, alkyl- or arylsulfonyl, nitro, and halogen;more preferably selected from alkyl, alkenyl, alkoxy, nitro, andhalogen; and most preferably selected from lower alkyl, lower alkoxy,and halogen. In one embodiment, each of groups R¹-R⁴ is phenyl,unsubstituted or substituted with a group selected from lower alkyl,lower alkoxy, and halogen. In specific embodiments, R¹-R⁴ are identicaland each is unsubstituted phenyl, α- or β naphthyl, o-tolyl, biphenyl,or p-methoxyphenyl.

[0081] The value of m is from 0 to 3, inclusive; m is preferably 1 or 3,and is most preferably 1. R⁵ and R⁶ represent one or more substituentson the respective N-heterocycles, independently selected from hydrogen,lower alkyl, lower alkenyl, lower alkynyl, and aryl. To avoid thepresence of additional chiral centers on the nitrogen heterocycles, eachgroup R⁵ and R⁶ is preferably hydrogen. However, the nitrogenheterocycles could be substituted such that chiral centers are notformed; i.e. by having two identical substituents at a given position,as in a gem-dimethyl group. Although not depicted in formula I, thenitrogen heterocycle may contain a further heteroatom, as in amorpholino ring.

[0082] In selected embodiments, each of R and R is selected fromhydrogen, lower alkyl, lower alkenyl, lower alkoxy, and halogen.Preferably, R⁵ and R⁶ are both hydrogen or both represent a gem-dimethylgroup; most preferably, R⁵ and R⁶ are both hydrogen.

[0083] R⁷ represents one or more groups on the phenyl ring independentlyselected from the group consisting of hydrogen, X as defined above, anda further fused ring, e.g. to form a naphthyl group. The substituentsdefined as group X for R₇ are preferably selected from alkyl, alkenyl,aryl, aralkyl, alkoxy, aryloxy, ester, amide, sulfonamide, alkyl- orarylsulfonyl, nitro, and halogen; and more preferably selected fromalkyl, alkenyl, alkoxy, aryl, aralkyl, aryloxy, and halogen. Multiplegroups R⁷ can be present and can be the same or different.

[0084] Representative ligands include compounds 1a-1n, as shown in FIG.1.

[0085] The stoichiometry of metal to ligand in the catalytic complex wasexamined via the evolution of ethane gas upon reaction of ligand 1a withEt₂Zn. Addition of two equivalents of Et₂Zn per ligand 1 liberated threeequivalents of ethane. Addition of water to this complex liberated thefourth equivalent of ethane. This observation supports a 2:1stoichiometry of metal ion to ligand in the complex. In addition,exposure of the complex to acetic acid in the inlet of an electrospraymass spectrometer produced a series of peaks consistent with the formulaC₄₅H₄₇N₂O₅Zn₂, i.e. a bimetallic zinc complex of 1a having boundacetate.

[0086] B. Preparation

[0087] B1. Ligand Synthesis

[0088] The availability of a variety of enantiomerically pure a-aminoacids provides a convenient route to the chiral α-amino alcohol moietyof the ligands. For example, an ester of L-proline (natural Sconfiguration) or D-proline (R configuration) was used to prepareligands 1a-1n, as described in Examples 1-13 below. The R- and S-isomersof other 2-carboxyl N-heterocycles, such as 2-azetidine carboxylic acid,2-piperidine carboxylic acid, and 1H-hexahydroazepine-2-carboxylic acid,are commercially available, and syntheses permitting preparation ofsubstituted derivatives have been reported (e.g. Seebach et al., 1989;Yazawa et al., 1998).

[0089] A convenient synthesis of ligands of formula I starts with2,6-hydroxymethylation of a phenol, as described, for example, in Vander Boom et al., 1998 and Arnaud et al., 1997 (reaction of p-cresol).Reaction of other para-substituted phenols is described in Examples 10and 11, below. Para-substituted phenols are preferred for this reaction(addition of formaldehyde) to preclude reaction at the para-position.Differently substituted 2,6-hydroxymethylated phenols can be prepared bymethods known in the art.

[0090] As shown in Examples 12A-B, for example,3,5-dimethyl-2,6-bis(hydroxymethyl)phenol (for ligand 1 m) was preparedvia the reaction of dimethyl acetonedicarboxylate with 2,4-pentanedione.Crisp et al., 2000, describes the preparation of2,6-bis(hydroxymethyl)phenol in high yield by LiAlH₄ reduction ofdimethyl (2-hydroxy isophthalate).

[0091] The primary hydroxyl groups of the 2,6-bis(hydroxymethyl)phenolcompound are converted to efficient leaving groups, e.g. bromide ortosylate. The resulting compound is then reacted with two equivalents ofa chiral 2-carboxy N-heterocycle. Addition of an aryl carbonnucleophile, such as an aryl Grignard reagent, is then employed toconvert each carboxyl group (preferably in ester form) to the tertiaryalcohols bearing groups R¹ to R⁴. This general route was used to prepareligands 1a-1c, 1g-h, and 1k, as described in Examples 1, 3-4,8-9 and 11,below.

[0092] Alternatively, N-B dc protected R- or S-proline, or another ofthe 2-carboxyl N-heterocycles noted above, is first reacted with an arylcarbon nucleophile, such as an aryl Grignard. The tertiary alcoholproduct is deprotected and reacted with a 2,6-bis(bromomethyl)phenolcompound. Examples of this route, used to prepare ligands 1a, 1d-f, 1j,and 1n, are described in Examples 2, 5-7, 10 and 13. The intermediatediphenylprolinol is commercially available. The route described inExamples 5-7 may be used to prepare other diarylprolinols.

[0093] During synthesis of variously substituted ligands, protectinggroups, as known in the art, may be used as necessary for any reactivesubstituents that may be present.

[0094] The following table gives the structures of ligands 1a-1n, where,in structure 1, m is 1 and R⁵ and R⁶ are hydrogen. Designation R⁷R^(I)-R⁴ 1a 4-methyl phenyl 1b 4-methyl 3,5-xylyl 1c 4-methyl 2-naphthyl1d 4-methyl 1-naphthyl 1e 4-methyl biphenyl 1f 4-methyl o-tolyl 1g4-methyl furyl 1b 4-methyl 4-methoxyphenyl 1j 4-nitro phenyl 1k4-methoxy phenyl 1m 3,5-dimethyl phenyl 1n 4-chloro phenyl

[0095] B2. Generation of Catalyst

[0096] The catalytic composition is formed by contacting a chiral ligandof formula I with a Group 2A or 2B metal compound which is capable ofgenerating a metal alkoxide upon reaction with an alcohol, andspecifically upon reaction with the hydroxyl groups of the ligands offormula I. Such compounds include dialkyl metals R₂M, alkyl (or alkenyl)metal halides RMX, metal alkoxides M(OR)₂, alkyl (dialkylamino) metalcompounds RMNR2, and alkyl (diarylamino) metals (where the groups R mayvary and are preferably lower alkyl or lower alkenyl). As noted above,preferred metals include Zn, Cd, Mg, Ca, and Ba. In one embodiment, thecompound is diethyl zinc; diphenylamino ethyl zinc (Ph2NZnEt) was alsoeffective.

[0097] The ratio of metal compound to ligand used for formation of thecatalyst is in the range of 1:1 (Tables 2-5 below) to 2:1 (Tables 1 and6 below). When ratios less than 2:1 are used, it is likely that excessligand is present in the catalyst solution.

[0098] The catalyst is preferably formed in an aprotic andnon-complexing solvent, such as, for example, THF, ether, acetone,toluene, other hydrocarbon solvents, chlorinated solvents, or a mixturethereof. Such solvents are generally suitable for carrying out the aldolreaction as well; therefore, a catalyst solution can be prepared andused directly, as described in the Examples below. For nitroaldolreactions, ether-based solvents such as THF, dioxane, DME and diethylether are preferred.

[0099] Typically, the catalyst is formed by combining a 1:1 to 2:1 ratioof metal compound and ligand in solution. (See e.g. Examples 14A, 15,17-18 and 20A.) A portion of the resulting solution is combined with theremaining reaction components, as described in the Examples below.Assuming a ratio of two metal atoms per ligand in the complex, the molarquantity of catalytic complex present in the reaction mixture would beone half the number of moles of metal compound.

[0100] III. Stereoselective Aldol Reactions

[0101] As demonstrated below, use of the catalytic complexes and methodsof the invention give aldol reaction products with highenantioselectivity starting from a variety of aldehyde substrates,including substrates with no branching and/or with unsaturation at thea:-carbon, which have historically given poor enantioselectivity inasymmetric addition reactions. In general, the aldehyde is of theformula RCHO, where R is selected from the group consisting of alkyl,cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, and aralkynyl. Ris optionally substituted, where preferred substituents are selectedfrom alkoxy, aryloxy, hydroxy, alkyl- or arylsulfonyl, sulfonamide,ester, amide, cyano, nitro, and halogen. While a-branched aldehydestypically give greater selectivity, the reaction is also successful withunbranched aldehydes, as shown below. A further advantage of the presentinvention is that the donor compound (nitroalkyl or ketone) need not beprovided in preactivated form.

[0102] A. Reactions with Ketone Donors

[0103] A large range of ketone donors may be used, as long as ana-hydrogen is present. The ketone is preferably of the formulaR′(C═O)CH₂Y, where Y is selected from hydrogen, hydroxy, alkoxy,aryloxy, amide, ester, alkyl- or arylsulfonyl, sulfonamide, halogen,aryl, and alkyl, and R′ is selected from alkyl, cycloalkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, and aralkynyl. R′ is optionallysubstituted, with preferred substituents selected from alkoxy, aryloxy,hydroxy, amide, alkyl- or arylsulfonyl, sulfonamide, ester, cyano,nitro, and halogen. In selected embodiments, Y is selected from hydrogenand hydroxyl, and R′ is selected from aryl, alkenyl, alkynyl, aralkenyl,and aralkynyl. Examples include aryl methyl ketones and aryl(hydroxymethyl) ketones.

[0104] The reactions can be performed over a wide temperature range; ingeneral, lower temperatures are expected to provide greater selectivitybut require longer reaction times. Temperatures of −35° C. to roomtemperature were found to be generally suitable, though temperaturesoutside this range can also be used.

[0105] A variety of solvents were found satisfactory, including thoseuseful for forming the catalyst, as noted above (e.g. THF, ether,acetone, toluene, other hydrocarbon solvents, and chlorinated solvents)as well as DMSO, DMF, and the protic solvent EPA (isopropanol). Additionof small amounts of EPA to reactions carried out in THF was found toincrease rate and yield.

[0106] It was found that turnover frequency was generally improved bythe addition of a small quantity of molecular sieves; e.g. about 50-500mg, preferably about 100-200 mg, per mmol of aldehyde. Pore size of themolecular sieves can vary, e.g. from about 3 to 6 Angstroms, as long asthe sieves are effective to trap water without trapping any significantamount of larger reaction components. In certain cases, the addition ofabout 5 to 15 mole % of a weak coordinating agent for zinc, such as atrialkyl phosphate, triarylphosphine oxide or triarylphosphine sulfide,was shown to improve both turnover and e.e.

[0107] Table 1 shows the results of a series of reactions employing avariety of aldehydes and ketones, and using the following reactionconditions (see general procedure in Example 14): ca. 5 mol % ligand 1a,ca. 10 mol % ZnEt₂, 15 mol % triphenylphosphine sulfide (Ph₃P═S), and 4Amolecular sieves (200 mg/mmol aldehyde) in THF. Reaction time was 2days, with the exception of entry 7 (4 days).

[0108] Absolute configurations were assigned by comparison to theliterature (see characterization data in Examples below) or by analogy.Enantiomeric excess was determined using chiral HPLC (Chiracel™ ODcolumn). TABLE 1 Enantioselective Aldol Reactions of Aryl Methyl Ketones

Entry No.  RCHO

Ketone: RCHO Temp, ° C.  Product Yield, % (e.e., %) 1a 1b

—Ph 10 −5 −15

33(56) 24(74) 2

—Ph 10 −5

49(68) 3

—Ph 10 5

62(98) 4

—Ph 10 5

60(98) 5

—Ph 10 5

79(99) 6

—Ph 10 5

67(94 major; 98 minor) 7

—Ph 10 5

61(93) 8

10 5

66(97) 9

10 5

48(97) 10

 5 5

36(98) 11

 5 5

40(96)

[0109] Lower ketone/aldehyde ratios generally gave good selectivity butlower yields. A 96% recovery of excess acetophenone was demonstrated forentry 3.

[0110] Improved e.e.'s were obtained on aldehydes without branch pointsat the (X-carbon by reducing the temperature of the reaction. In theremaining reactions, as can be seen, very high e.e.'s were routinelyobtained. Using a chiral but racemic aldehyde, 2-phenylpropenal (entry6), a 2:1 diastereomeric mixture of adducts, both having high e.e., wasobtained.

[0111] Table 2 shows results of reaction of a less sterically demandingketone, acetone, with various aldehydes. The reactions shown in Table 2were performed with both ligands 1a and 1m (in which the 4-methyl phenolof 1a is replaced with 3,5-dimethyl phenol). Standard conditions were0.5 mmol aldehyde, 0.5 ml (approx. 6.8 mmol) acetone, 100 mg 4 Åmolecular sieves, a reaction temperature of 5° C., and catalyst added asa 0.1 M solution in THF. (See Example 15.) In certain reactions, 5 eq ofPPh₃S per eq of catalyst were added, as indicated.

TABLE 2 Enantioselective Aldol Reactions of Acetone with VariousAldehydes Mol % Ratio Yield catalyst; elim: aldol e.e. Entry AldehydeLigand additive Product aldol (%) (%) 1

1a 1m 5 10 10

0 0 0 62 85 89 87 93 92 2

1a 1m 5 10

0 0 80 89 87 91 3

1a 1m 5 10

0 0 76 72 86 94 4

1a 1a 1m 5 10 10

0 0 0 79 72 84 82 87 91 5

1a 1m 5 10

0 0 24 59 76 84 6

1a 1a 1m 5 10 10

1:6 3:1 1:15 59 24 76 89 89 82 7

1a 1a 1m 1m 5 5; 5 eq PPh₃S 10 10; 5 eq PPh₃S

0 1:15 0 0 56 55 69 72 84 87 89 84 8

1a 1a 1m 1m 5 5; 5 eq PPh₃S 5 10

1:3 1:3 0 4:1 55 57 78 (82) 12 88 85 83 79 9

1a 1a 1m 5 5 10

1:2 0 1:8 36 62 (80) 54 74 78 76

[0112] Yields are isolated yields, with conversions given inparentheses. Product ratios were determined by ¹H NMR spectroscopy ofthe crude product, and e.e.'s by chiral HPLC using chiracell OD or OJcolumns. Absolute configurations were assigned by comparison to theliterature or by analogy. (See characterizing data in Examples, below.)

[0113] With the exception of entry 1, somewhat improved results wereobtained using ligand 1 m over 1a under otherwise identical conditions.For an α-branched aldehyde (entry 4), a slight improvement in yield anda significant improvement in e.e. was obtained. In the difficult casesof a-unbranched and aryl aldehydes, significant improvements arose usingligand 1 m. In all cases (entries 5-9), improvements in yields wereobtained, frequently due to a decrease in the elimination side product.In some cases, notably entry 5, e.e. was also higher with ligand 1 m.

[0114] Enantioselectivities observed in reaction of branched aldehydeswith acetophenone were higher than those shown in Table 2 for acetone.For example, e.e.'s for the reaction products of the aldehydes ofentries 1, 2, and 4 with acetophenone were 98-99%. Absoluteconfigurations were the same for the acetone and acetophenone reactionproducts.

[0115] For α-unbranched aldehyde substrates, the catalysts derived fromreaction of ligand 1 a or 1 m with 2 eq of diethylzinc give the bestrecorded results to date. In comparative reactions using proline as thechiral auxiliary, the unbranched aldehydes shown in Table 2 gave aldolproducts in yields and e.e.'s ranging from 22-35% and 36-73%,respectively. Reactions using ligand 1m, in contrast, gave yields-ande.e.'s from 59-76% and 82-89%, respectively. The results are alsoconsiderably improved over the use of Ipc-X (Ipc=isopinocampheyl; X═C1or OSO₂CF₃) as a chiral auxiliary, which must be used in stoichiometricquantities (Ramachandran et al.; Paterson et al.).

[0116] Methyl vinyl ketone has been recognized as a useful buildingblock in organic synthesis. Therefore, the aldol reaction of MVK as anucleophile was also examined, using a zinc complex of ligand 1 a ascatalyst. The reaction employed 0.5 mmol cyclohexane carboxaldehyde andca. 10 mol % ligand/10 mol % metal (see Example 16). Products with highenantiomeric excess were obtained, as shown. Dehydration of the aldolproduct, however, decreased the yields. TABLE 3 Enantioselective AldolReaction of MVK with Cylohexanecarboxaldehyde MVK, Additive, Temp,Yield, e.e., Entry mL mL Solvent ° C. Time % % 1 0.5 none THF 0 4h 34 912 0.21 IPA, 0.2 THF 0 3h 20 90 3 0.5 IPA, 0.2 THF 0 4h 37 90 4 0.5 MS4A, THF 0 4h 37 91 100 mg IPA, 0.2 5 0.5 MS 4A, THF −25 2d 35 90 100 mgIPA, 0.2 6 1 MS 4A, MVK −25 2d 65 94 100 mg IPA, 0.2

[0117] Reactions of acetone and MVK as ketone donors were also conductedusing different chiral ligands. The results are shown in Table 4. Thealdehyde substrate in these reactions was cyclohexanecarboxaldehyde (0.5mmol). They also employed ca. 10 mol % chiral ligand/10 mol % metal (seeExample 17). The reactions of entries 9 and 10 employed 100 mg of 4Amolecular sieves (MS). TABLE 4 Enantioselective Aldol Reactions ofAcetone and MVK using Various Ligands Additive, Temp, Yield, e.e., EntryLigand Ketone, mL mL Solvent ° C. Time % % 1 1b acetone, 1.5 noneacetone 0 15 h 39 45 2 1b acetone, 1 IPA, 0.5 acetone 0 15 h 74 40 3 1cacetone, 1 IPA, 0.5 acetone 0 15 h 47 60 4 1c MVK, 1 IPA, 0.5 MVK 0 15 h52 80 5 1g acetone, 1 IPA, 0.5 acetone 0  3 d 28 35 6 1h MVK, 1.3 IPA,0.2 MVK −30  3 d 57 73 7 1j acetone, 0.5 IPA, 0.2 THF r.t. 18 h 14 53 81k acetone, 0.5 4A MS THF 0  4 h 59 72 IPA, 0.2 9 1k MVK, 1.3 IPA, 0.2MVK −30  4 d 44 82 10 1m acetone, 0.5 4A MS THF −8  2 d 48 86 Ph₃P = S,15%

[0118] In this series of reactions, ligands 1c and 1m gave the higheste.e.'s at moderate temperatures. Reactions with ligands based onp-cresol, similar to 1 a, but having larger aryl group on the tertiaryalcohol groups, gave results similar to or somewhat superior to thoseusing 1a. These ligands include naphthyl ligands 1 c-d and biphenylligand 1 e (data not shown for 1d-1e).

[0119] See also section B3, below, for further discussion of variationsin ligand structure.

[0120] Traditionally, α-hydroxyketones have been particularlyinteresting synthetic subunits, due to the desirability of thepolyoxygenated products, but they have presented seriouschemoselectivity problems in aldol reactions. Reactions using thepresent catalysts, however, were very effective, giving high yields ande.e.'s in asymmetric aldol reactions with a wide range of aldehydes,including branched and non-branched. These reactions also gave highyields from nearly stoichiometric ketone/aldehyde ratios. Surprisingly,the enantiofacial selectivity with respect to the aldehyde was oppositeto that observed with the methyl ketones, above (Table 1).

[0121] Table 5 shows results of the reaction of hydroxyacetophenone andcyclohexane carboxaldehyde, in a 1.5:1 molar ratio, in the presence of2.5 to 5 mole % catalyst (prepared by reacting equimolar amounts ofligand 1a and diethylzinc in THF). Reactions were run on a 0.5 mmolscale at 0.3M aldehyde, in the presence of 100 mg 4A molecular sievesand 15 mole % Ph₃PS.

[0122] The reaction gave a high yield of the desired aldol product, withhigh diastereoselectivity, favoring the syn adduct as shown(d.r.=diastereomeric ratio). Lowering reaction temperature improved e.e.dramatically. In contrast to results observed with acetophenone, thepresence or absence of Ph₃PS at −35° C. had no effect (entries 6-7).

[0123] Diastereomeric ratio (dr) was largely invariant with respect totemperature. However, it was found, remarkably, that lowering thecatalyst load to 2.5 mol % (entry 8) gave a significant increase indiastereoselectivity with no appreciable loss in yield.

[0124] The relative and absolute stereochemistry of the majordiastereomer was established by comparison to the product as derivedfrom an asymmetric dihydroxylation (see Example 15). Strikingly, theabsolute configuration of the stereocenter derived from the aldehyde isopposite to that obtained using acetophenone as donor. TABLE 5Enantioselective Aldol Reaction of α-Hydroxyacetophenone

Mol % 15 mol % Temp, Time Isolated e.e. Entry catalyst Ph₃PS ° C. (h)Yield (%) d.r. (%) 1 5.0 yes r.t. 48 >90 5:1 30 2 5.0 yes 5 15 82 5:1 453 5.0 yes −5  48 >90 5:1 76 4 5.0 yes −25 48 >90 5:1 88 5 5.0 yes −35 2494 5:1 90 6 5.0 no −35 24 97 5:1 90 7 5.0 no −55 48 77 5:1 93 8 2.5 no−40 24 83  30:1 92

[0125] Table 6 illustrates the versatility of this reaction using avariety of aldehyde substrates. Reactions were run on a 0.5 mmol scaleat 0.3M aldehyde, in the presence of 2.5 to 5 mole % catalyst (preparedas described in Example 18) and 100 mg 4A molecular sieves. Reactionswere carried out at −35° C. for 24 h, unless otherwise indicated. Thereaction of entry 6 was carried out at −55° C. Yields are isolatedyields.

[0126] Notably, the reaction gave high e.e.'s from unbranched substrates(entries 5-8 and 10).

[0127] Decreasing the temperature (entry 6) gave an increase in e.e., aswell as diastereoselectivity. Reactions with 2-hydroxyacetylfuran as thedonor ketone also gave excellent results (entries 9 and 10).

[0128] Reducing the ratio of substrates from 1.5:1 to 1.3:1 (entries 9aand 10) had no deleterious effect on conversion or chemoselectivity. Asshown in entry 2a vs. 2b, reducing this ratio further to 1.1:1.0decreased conversion, but both the diastereoselectivity andenantioselectivity increased. A similar trend was observed with3-methylbutanal (entry 4a vs. 4b).

[0129] In all cases examined (entries 1-5), dropping the catalyst loadfrom 5 to 2.5 mol % increased diastereoselectivity and, in some cases(entries 2-4), e.e. significantly. TABLE 6

Enantioselective Aldol Reactions of α-Hydroxyketones with VariousAldehydes Ketone: Mol % Yield e.e. R Ar RCHO cat Major product (%) d.r.(%) 1

Ph 1.5 2.5 5.0

83 97 30:1 5:1 92 90 2a 2b

Ph 1.5 1.1 2.5 5.0 5.0

89 93 72 13:1 5:1 6:1 93 86 93 3

Ph 1.5 2.5 5.0

74 97 one product 13:1 96 81 4a 4b

Ph 1.5 1.1 2.5 5.0 5.0

65 96 79 35:1 3:1 4:1 94 88 93 5a 5b

Ph 1.5 1.1 2.5 5.0

78 98 9:1 3:1 91 90 6

Ph 1.5 5.0

62 3.5:1 96 7

Ph 1.5 5.0

89 5:1 86 8

Ph 1.5 5.0

91 5:1 87 9a 9b

1.3 1.5 5.0

90 77 6:1 6:1 96 98 10

1.3 5.0

97 3.4:1 95

[0130] An advantage of the asymmetric aldol reaction over asymmetricdihydroxylation in producing chiral 1,2-diols is the formation of bothstereocenters simultaneous with carbon-carbon bond formation. Further,in an asymmetric dihydroxylation, chemoselectivity issues could arisewith olefinic substrates, such as that of Table 3, entry

[0131] The reaction described above approaches the ideal atom economicalversion of the asymmetric aldol reaction, employing near-stoichiometricamounts of substrate and donor and catalytic amounts of other reagents.Excellent conversion and chemoselectivity was observed withketone/aldehyde ratios as low as 1.1:1.0.

[0132] B. Nitroalkyl Donors (Nitroaldol or Henry Reaction)

[0133] The nitroaldol reaction provides a method of forming acarbon-carbon bond under relatively mild conditions with the concomitantformation of two asymmetric centers. The resulting β-nitroalcoholproduct is amenable to further transformation to additional usefulstructures, e.g. by reduction of the nitro group, oxidation of thealcohol, etc. In accordance with the present invention, the nitroaldolreaction can be carried out between an aldehyde and a nitroalkylcompound with high stereoselectivity.

[0134] As noted above, a “nitroalkyl” compound refers to a compoundwhich contains a nitromethyl (—CH₂NO₂) or nitromethylene (>CHNO₂) moietyand is able to form a stable carbanion on abstraction of an α-hydrogen,the simplest example being nitromethane (CH₃NO₂). Nitroaldol reactionscan also been carried out on nitroalkyl compounds which include otherfunctional groups, such as alcohols, ethers, including acetals andketals, thioethers, ketones, esters, including α- and β-esters, acyloxygroups, amines, amides, and imides (see the 2001 review article byLuzzio, cited above). Such substrates are expected to be suitable forthe reactions described herein, keeping in mind that when CL-branchingis present (i.e. a nitromethylene compound), mixtures of diastereomersmay be formed.

[0135] 1. Reaction Parameters

[0136] Table 7 shows the results of a series of reactions of cyclohexanecarboxaldehyde with nitromethane using catalyst 1 a. A 0.1 M catalystsolution, which may be prepared as described in Example 20A, was addeddirectly to the reaction solution containing nitromethane and thealdehyde substrate. All reactions were run on a 1 mmol scale at 0.33 Min aldehyde in the solvent shown, containing about 100 mg of 4Amolecular sieves per 1 mmol of aldehyde. Reactions were carried out for24 hrs (see Example 20B). Enantiomeric excess of the products wasdetermined by chiral IIPLC. TABLE 7 Nitro Aldol Reaction betweenNitromethane and Cyclohexanecarboxaldehyde

Yield eq. Mol % %/ee Entry CH₃NO₂ catalyst Temp, ° C. Solvent % 1 10 5 5THF 69/78 2 10 5 −20 THF 68/85 3 10 5 −20 Toluene 68/57 4 10 5 −20CH₂Cl₂ 75/51 5  2 5 −20 Et₂O 20/55 6  2 5 −20 THF/dioxane, 4:1 17/86 710 5 −78 then −20 THF 75/85 8 10 2.5 −78 then −20 THF 44/85 9  6 5 −78then −20 THF 70/86

[0137] While only small amounts of catalyst (e.g. 2.5 mole %, entry 8)were effective to give high e.e.'s, about 5 mole % catalyst, along withabout 5 equivalents of the nitroalkyl compound relative to aldehyde,were needed to give high conversions. In the cases where low yields wereobtained (entries 5, 6 and 8), the aldehyde was recovered unchanged.

[0138] While moderate enantioselectivity was obtained at 5° C.,significant improvements were seen upon lowering the temperature.Preferably, the reaction mixture is cooled at −78° C. during addition ofthe catalyst (entries 7-9), and the reaction allowed to proceed at atemperature of about −60° C. to −20° C. In similar reactions run withisopropyl and pivalyl aldehyde, an absolute increase in e.e. of 5% wasseen in both cases on going from a reaction temperature of-25° C. to−60° C. (isopropyl 83% to 88%; pivalyl 88% to 93%).

[0139] A clear benefit was also observed from the use of coordinatingpolar solvents such as THF, DME and dioxane.

[0140] 2. Aldehyde Substrate

[0141] As shown in Table 8, the reaction is effective for conventionallychallenging substrates such as α-unbranched and α,β-unsaturatedaldehydes. All reactions in the Table were carried out on a 1 mmol(aldehyde) scale, using 5 mol % catalyst (prepared from ligand 1a, asdescribed in Example 20A) and 10 eq. CH₃NO₂ in 0.33 M THF solution,containing about 100 mg of 4A molecular sieves per 1 mmol of aldehyde(RCHO), at −35° C. for 24 hr, unless noted otherwise. TABLE 8Enantioselective Nitroaldol Reactions of Various Aldehydes with CH₃NO₂Entry R Product Yield (%) ee (%) 1

58 88 2

88 93 3

90 92 4

84 87 5a 5b

56 59 85 84 6

56 86 7

81 dr. = 19:1 8

75 91 9

71 93 10

69 78 11

79 90

[0142] Enantiomeric excess was determined by chiral HPLC. The e.e. ofthe product of entry 5 was increased to 96% by one recrystallization.Absolute stereochemistry of the products was determined by comparison toliterature values and/or by NMR analysis of the (S)—O-methylmandelatederivatives (see e.g. Example 21).

[0143] α-Branched aldehydes gave nitro aldol products in high yields ande.e. (entries 1-3). Entries 1-2 were carried out at −60° C., using only5 eq. CH₃NO₂. Reasonable yields were obtained from α-unbranchedaldehydes by increasing the nitroalkane/adhehyde equivalent ratio to 15and by performing the reaction using more concentrated solutions(entries 5 and 6). Reaction 5a was performed using 15 eq. CH₃NO₂ and 5mol % catalyst in 0.66 M THF solution for 2 days; reactions 5b and 6were performed using 15 eq. CH₃NO₂ and 10 mol % catalyst in 0.33 M THFsolution for 2 days.

[0144] Enantiomerically pure (R)-citronellal (entry 7) gave the nitroaldol product in high yield and high diastereomeric ratio. However,(S)-citronellal gave the corresponding product (not shown) in 51% yieldand 9.6:1 diastereomeric ratio. Aromatic and heterocyclic aldehydes gavenitro aldol products in good yields and good e.e. as well (entries8-11).

[0145] 3. Ligand Variations

[0146] The reaction of Entry 10 in Table 8 was also carried out withcatalysts prepared from different ligands. When the 4-methyl group ofligand 1 a was replaced with fluorine, an increase in e.e. to 85% wasobserved. Similar increases were observed when the phenyl groups on thediaryl carbinol moieties of 1a were replaced with 4-fluorophenyl,p-biphenyl, or 2-naphthyl.

[0147] 4. Further Reactions

[0148] The catalyst system reported herein allows efficient and atomeconomical access to enantiomerically enriched α-hydroxy amines andα-hydroxy acids which are important building blocks in organicsynthesis.

[0149] The product of entry 6 is a useful bifunctional molecule thatcould serve, for example, as starting material for the rapid productionof “GABOB” (γ-amino-β-hydroxy butyric acid). The product of entry 10could be used as starting material for the synthesis of arbutamine.

[0150] The nitro aldol products can also be further elaborated intochiral α-hydroxy acids (Matt el al.) without epimerization of thestereogenic center (see below and Examples 22-23).

EXAMPLES

[0151] The following examples illustrate but are not intended in any wayto limit the invention.

Example 1 Synthesis of Ligand 1a

[0152] A. Synthesis of compound 2, 2,6-bis(hydroxymethyl)-p-cresol (seeVan der Boom et al., J. Am. Chem. Soc. 1998, 120, 6531; Arnaud et al.,Tetrahedron 1997, 53, 13757).

[0153] To a solution of p-cresol (54 g, 500 mmol) in aqueous NaOHsolution (25 g of NaOH in 100 mL of water) was added a solution of 37%formaldehyde in water (108 g, 100 mL) at room temperature, and themixture was stirred at the same temperature for 15 h. The mixture wasfiltered, and the precipitate was dissolved in water. Acetic acid wasadded to neutralize, and the precipitated crystals were filtered, washedwith water and dried under vacuum (35.5 g, 211 mmol, 41%). Spectroscopicdata was in good accordance with literature values.

[0154] B. Synthesis of Compound 3, 2,6-Bis(bromomethyl)-p-cresol (seeVan der Boom, Above).

[0155] To compound 2 (4.1 g, 24.4 mmol) was added HBr in acetic acid (22mL) at room temperature, and the mixture was stirred at the sametemperature for 24 h. Water was added to the reaction mixture, and themixture was filtered. The filtered solid was washed with water and driedunder vacuum (5.9 g, 20 mmol, 82%). Spectroscopic data was in goodaccordance with literature values.

[0156] C. Synthesis of Compound 4.

[0157] To a solution of L-proline methyl ester hydrochloride (6.36 g,38.4 mmol) and triethylamine (8.1 g, 11.2 mL, 80 mmol) in CH₂Cl₂ (60 mL)was added a solution of 3 (4.7 g, 16 mmol) in CH₂Cl₂ (20 mL) at roomtemperature, and the mixture was stirred at the same temperature for 24h. The mixture was concentrated to half volume under vacuum, the residuewas purified by silica gel column chromatography (pet:AcOEt, 1:1) togive 4 (5.32 g, 13.6 mmol, 85%).

[0158] IR (neat) ν cm⁻¹; 2951, 2823, 1739, 1614, 1479, 1436, 1272, 1202,1039, 1009. ¹H NMR (300 MHz, CDCl₃) δ; 9.95 (bs, 1H), 6.85 (s, 2H), 3.96(d, J=12.9 Hz, 2H), 3.70 (s, 6H), 3.61 (d, J=12.9 Hz, 2H), 3.28 (dd,J=8.8, 6.4 Hz, 2H), 3.06 (ddd, J=10.0, 7.1, 2.9 Hz, 2H), 2.42 (q, J=8.8Hz, 2H), 2.21 (s, 3H), 2.20-1.72 (m, 8H). ¹³C NMR (75 MHz, CDCl₃) δ;174.5, 153.4, 129.5, 127.3, 122.9, 65.0, 54.3, 52.9, 51.9, 29.5, 23.1,20.4. HRMS. Calcd for C2₁H₃₀N₂O₅ (M⁺) 390.2154, found 390.2150.

[0159] D. Synthesis of Ligand 1a.

[0160] To a solution of compound 4 (6.8 g, 17.4 mmol) in THF (60 mL) wasadded a solution of phenylmagnesium chloride (2 M in THF, 78 mL, 156.6mmol) at room temperature, and the mixture was stirred at the sametemperature for 1 day. Sat. NH₄Cl was added to the reaction mixture, andthe mixture was extracted with ether. The The organic layer was washedwith brine and dried over magnesium sulfate. Evaporation of the solventunder reduced pressure and purification of the residue by silica gelcolumn chromatography (pet:AcOEt, 9:1-4:1) afforded 1a (8.2 g, 12.9mmol, 74%). t_(r)=7.27 min (major enantiomer) and 12.50 min, (ChiralcelOD, λ=254 nm, heptane:isopropanol=80:20, 1 ml/min). [α]_(D) ²⁵+49.8 (c3.0, CHCl₃, 99.7% ee). IR (neat) ν cm⁻¹; 3362, 3058, 3025, 2972, 2869,1598, 1479, 1448, 1117. ¹H NMR (300 MHz, CDCl₃) δ; 7.70 (d, J=7.6 Hz,4H), 7.57 (d, J=7.6 Hz, 4H), 7.36-7.10 (m, 12H), 6.60 (s, 2H), 3.97 (dd,J=9.0, 4.6 Hz, 2H), 3.40 (d, J=12.7 Hz, 2H), 3.23 (d, J=12.7 Hz, 2H),2.88-2.76 (m, 2H), 2.39 (q, J=9.5 Hz, 2H), 2.16 (s, 3H), 2.10-1.40 (m,8H). ¹³C NMR (75 MHz, CDCl₃) δ; 152.6, 147.0, 146.4, 128.8, 128.2,128.0, 127.1, 126.6, 126.4, 126.0, 125.9, 124.0, 78.9, 71.4, 57.7, 55.0,29.6, 24.0, 20.4. MS(SIMS) 639.3 (M⁺+1), 638.3 (M⁺). HRMS. Calcd forC₃₀H₃₅N₂O₂ (M⁺−Ph₂COH) 455.2699, found 455.2692.

Example 2 Synthesis of Ligand 1 a (Alternate Route)

[0161]

[0162] To a solution of diphenylprolinol (253 mg, 0.1 mmol) andtriethylamine (0.14 mL, 1 mmol) in CH₂Cl₂ (2 mL) was added a solution of3 (134 mg, 0.455 mmol) in CH₂Cl₂ (2 mL) at room temperature, and themixture was stirred at the same temperature for 24 h. The mixture wasconcentrated to half volume under vacuum. Purification of the residue bysilica gel column chromatography (pet:AcOEt, 4:1) afforded 1a (230 mg,0.36 mmol, 79%).

Example 3 Synthesis of Ligand 1b

[0163]

[0164] To a solution of compound 4 (500 mg, 1.28 mmol) in THF (5 mL) wasadded a solution of 3,5-dimethylphenylmagnesium bromide (2M in THF, 6.5mL, 13 mmol) at room temperature, and the mixture was stirred at thesame temperature for 2 days. Sat. NH₄Cl was added to the reactionmixture, and the mixture was extracted with ether. The organic layer wasextracted with 1N HCl, and water layer was washed with ether. Conc.NH₄OH was added to the water layer, and the mixture was extracted withether. The organic layer was washed with brine and dried over magnesiumsulfate. Evaporation of the solvent under reduced pressure andpurification of the residue by silica gel column chromatography(pet:AcOEt, 4:1) afforded 1b (396 mg, 0.492 mmol, 38%). ¹H NMR (300 MHz,CDCl₃) δ; 7.23 (s, 4H), 7.15 (s, 4H), 6.81 (s, 2H), 6.70 (s, 2H), 6.55(s, 2H), 3.85 (dd, J=9.0, 4.4 Hz, 2H), 3.19 (d, J=12.9 Hz, 2H), 3.08 (d,J=12.9 Hz, 2H), 2.88-2.78 (m, 2H), 2.50-1.52 (m, 10H), 2.30 (s, 12H),2.23 (s, 12H), 2.15 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ; 152.5, 147.0,146.3, 137.4, 137.3, 128.8, 128.2, 128.0, 127.0, 124.0, 123.7, 123.6,78.7, 71.6, 57.1, 55.2, 29.7, 24.2, 21.7, 21.6, 21.5, 20.5. MS(SIMS)751.3 (M⁺+1), 750.3 (M⁺).

Example 4 Synthesis of Ligand 1c

[0165]

[0166] A solution of compound 4 (1 g, 2.56 mmol) in THF (5 mL) was addedto a solution of β-naphthyl magnesium bromide (IM in THF, 17.9 mL, 17.9mmol) at 0° C., and the mixture was stirred at room temperature for 15h. Sat. NH₄Cl was added to the reaction mixture, and the mixture wasextracted with ether. The organic layer was washed with brine and driedover magnesium sulfate. Evaporation of the solvent under reducedpressure and purification of the residue by silica gel columnchromatography (pet:AcOEt, 4:1-1: 1) afforded 1c (1.5 g, 1.79 mmol,70%). IR (neat) ν cm⁻¹; 3346, 3056, 2972, 2870, 1949, 1914, 1740, 1628,1599, 1478, 1269, 1122. ¹H NMR (300 MHz, CDCl₃) δ; 8.41 (s, 2H), 8.14(s, 2H), 7.98-7.32 (m, 24H), 6.45 (s, 2H), 4.19 (dd, J=9.3, 5.1 Hz, 2H),3.39 (d, J=12.7 Hz, 2H), 3.16 (d, J=12.7 Hz, 2H), 2.82-2.72 (m, 2H),2.37 (dt, J=9.5, 6.8 Hz, 2H), 2.16-1.55 (m, 8H), 2.03 (s, 3H). ¹³C NMR(75 MHz, CDCl₃) δ; 152.8, 144.3, 143.8, 133.2, 133.1, 128.9, 128.4,128.3, 127.8, 127.8, 127.7, 127.4, 127.3, 126.9, 125.9, 125.7, 124.8,124.7, 124.5, 124.4, 123.7, 79.2, 70.7, 57.6, 55.1, 29.8, 24.0, 20.2.MS(SIMS) 839.4 (M⁺+1).

Example 5 Synthesis of N-Benzyl (S)-Proline Methyl Ester 5

[0167]

[0168] Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to astirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) inMeOH (86 mL). After the addition, the ice bath was removed and thestirring was continued for 15 h at room temperature. The solvent wasthen evaporated and the residual oil redissolved in dry CH₃CN (70 mL).Et₃N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added toobtain a white suspension. After 12 h of stirring at room temperature,the CH₃CN was evaporated, and the residue was partitioned betweensaturated NH₄Cl (200 mL) and Et₂O (200 mL). The phases were separated,the aqueous layer was extracted with Et2O (40 mL×2), and the combinedorganic phases were washed with water and brine, dried (MgSO₄), andconcentrated. The residue was purified over silica gel using 5 to 10%EtOAc/pet ether to give a clear oil (6.37 g, 69%): ¹H NMR (300 MHz,CDCl₃) δ 1.70-2.20 (m, 4H), 2.32-2.46 (m, 1H), 3.00-3.10 (m, 1H),3.20-3.30 (m, 1H), 3.56 (d, J=12.7 Hz, 1H), 3.64 (s, 3H), 3.88 (d,J=12.7 Hz, 1H), 7.25-7.35 (m, 5H). The spectroscopic data agrees withliterature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56,442).

Example 6 Synthesis of Ligand 1e

[0169] A. Preparation of Bis(biphenylyl)-(s)-prolinol

[0170] A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THFwas prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and onecrystal of 12 in THF (10 mL). The Grignard reaction was initiated withthe aid of gentle warming by a heat gun. After the iodine color haddissipated, the remaining 30 mL of bromide solution was added dropwiseto the reaction mixture. After the reflux subsided, the solution waswarmed over an oil bath (70° C.), for 30 minutes, then cooled to 0° C.N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL)was added. After the addition, the solution was allowed to warm to roomtemperature and stirred for another 8 hours. Saturated NH₄Cl (150 mL)was added and the resulting mixture was diluted with Et₂O (200 mL). Thephases were separated and the organic phase was washed with H₂O andbrine, dried (MgSO₄), and concentrated. The residue was purified over ashort silica gel column using 5 to 20% EtOAc/pet ether to a give a whitesolid, which was recrystalized with CH₂Cl₂/pet ether to obtain whiteneedles (4.106 g, 83%): mp 85-86° C., ¹H NMR (300 MHz, CDCl₃) δ1.60-1.74 (m, 2H), 1.76-1.88 (m, 1H), 1.94-2.08 (m, 1H), 2.40 (dd,J=16.6, 9.0 Hz, 1H), 2.92-3.00 (m, 1H), 3.10 (d, J=12.7 Hz, 1H), 3.38(d, J=12.5 Hz, 1H), 4.06 (dd, J=9.3, 4.6 Hz, 1H), 5.04 (s, 1H),7.04-7.60 (m, 14H), 7.68 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H).

[0171] 10% Pd/C (0.30 g) was added in one portion to a stirred solutionof the N-benzyl compound (1.25 g, 2.32 mmol) and NH₄HCO₂ (0.88 g, 13.96mmol) and EtOAc (5 mL) under Ar. After 1 hour, the suspension wasfiltered through a pad of Celite using MeOH as rinse. The solvent wasevaporated and the residue was purified over a short silica gel columnto give an off white solid (0.523 g, 56%) which was recrystalized fromEtOAc/pet ether to obtain white needles: [α]²⁵ _(D)−51.95 (c 7.83,CH₂Cl₂), FTIR (CH₂Cl₂ cast) 3363, 2973, 1599, 1485 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 1.60-1.90 (m, 4H), 2.90-3.10 (m, 2H), 4.33 (t, J=8.2 Hz,1H), 7.30-7.72 (m, 18H); ¹³C NMR (300 MHz, CDCl₃) δ 25.53, 26.35, 46.79,64.54, 77.43, 125.92, 126.26, 126.75, 127.01, 127.13, 128.64, 128.69,139.17, 139.35, 140.76, 140.87, 144.43, 147.18.

[0172] B. Synthesis of Ligand 1e.

[0173] Dibromide 3 (0.175 g, 0.60 mmol) (see Example 1B) was added inone portion to a stirred and cooled (0° C.) solution of (S)—bis(biphenylyl)prolinol, above (0.51 g, 1.258 mmol) and K₂CO₃ (0.345 g,2.50 mmol) in dry DMF (3 mL). The solution was allowed to warm to roomtemperature and stirred for 12 h. The mixture was partitioned with Et₂O(50 mL) and water (30 mL). The aqueous phase was extracted with Et₂O (10mL×2) and the combined organic phases were washed with water and brine,dried (MgSO₄) and concentrated. The residue was purified over grade IIIalumina using 5 to 15% EtOAc/pet ether to give a yellow oil. The oil wasredissolved in CH₂Cl₂ and dried over Na₂SO4 and the solvent wasevaporated. The product was azeotroped with benzene (10 mL×2) to obtaina white powder (0.42 g, 74%): [α]²⁵ _(D)+86.51 (c 1.58, CH₂Cl₂); FTIR(CH₂Cl₂ cast) 3425, 1636, 1448 cm¹; ¹H NMR (300 MHz, CDCl₃) δ 1.42-1.50(m, 4H), 1.56-1.90 (m, 2H), 1.96-2.04 (m, 2H), 2.13 (s, 3H), 2.42 (dd,J=16.1, 9.5 Hz, 2H), 2.76-2.88 (m, 2H), 3.24 (d, J=12.7 Hz, 2H), 3.58(d, J=12.9 Hz, 2H), 4.02 (dd, J=9.0, 5.1 Hz, 2H), 6.06 (s, 2H),7.22-7.60 (m, 12H), 7.68 (d, J=9.0 Hz, 4H), 7.82 (d, J=9.0 Hz, 4H); ¹³CNMR (75.5 MHz, CDCl₃) δ 23.86, 29.66, 54.99, 57.86, 71.25, 78.66,124.05, 126.33, 126.42, 126.76, 126.99, 127.20, 128.59, 128.67, 129.04,139.17, 139.35, 140.63, 140.79, 145.55, 146.21, 152.79.

Example 7 Synthesis of Ligand 1f

[0174] A. Preparation of Bis(o-tolyl)-(S)-prolinol

[0175] o-Tolylmagnesium bromide (7.32 mL, 1 M in THF, 7.32 mmol) wasadded dropwise to a stirred and cooled (0° C.) solution of ester 5(0.617 g, 2.81 mmol) in THF (5 mL). After the addition, the resultingsolution was allowed to warm to room temperature and stirred for 8hours. Saturated NH₄Cl (10 mL) was added and the mixture was partitionedwith Et₂O (30 mL) and water (10 mL). The organic layer was washed withwater and brine, dried (MgSO₄), and concentrated. The residue waspurified over silica gel using 5 to 10% EtOAc/pet ether to obtain an oil(0.869 g, 83%).

[0176] 10% Pd/C (0.18 g) was added in one portion to a stirred solutionof the above product (0.743 g, 2.00 mmol) and NH₄HCO₂ (1.51 g, 24.01mmol) in MeOH (10 mL) under Ar. After 8 hours, the mixture was filteredthrough a pad of Celite using MeOH as rinse. The solvent was evaporatedand the residue was purified by silica gel using EtOAc to give XX as anoil (0.46 g, 82%): [ ]²⁵ _(D)−149.35 (c 1.52, CH₂Cl₂), FTIR (CH₂Cl₂cast) 3385, 3054, 2986, 1601 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.30-1.44(m, 1H), 1.60-1.84 (m, 3H), 2.02 (s, 3H), 2.08 (s, 3H), 3.06 (t, J=5.93Hz, 1H), 4.30-4.42 (m, 1H), 6.92-7.20 (m, 6H), 7.46 (d, J=7.1 Hz, 1H),7.76 (br s, 1H); ¹³C NMR (75.5 MHz, CDCl₃) δ 21.65, 21.95, 25.56, 27.47,46.59, 62.24, 78.85, 124.68, 124.72, 126.55, 126.60, 126.88, 128.15,131.76, 132.80, 142.38, 144.19.

[0177] B. Synthesis of Ligand 1f.

[0178] Dibromide 3 (0.262 g, 0.84 mmol) (see Example 1B) was added inone portion to a stirred and cooled (0° C.) solution ofbis(o-tolyl)(S)-prolinol, above (0.494 g, 1.75 mmol) and K₂CO₃ (0.47 g,3.40 mmol) in dry DMF (3 mL). The solution was stirred at roomtemperature for 12 h, then partitioned with Et₂O (20 mL) and water (10mL). The aqueous layer was extracted with Et₂O and the combined organicphases were washed with water and brine, dried (MgSO₄) and concentrated.The residue was purified over grade III alumina using 5 to 10% EtOAc/petether to give an oil, which was redissolved in CH₂Cl₂ and dried overNa2SO4. After evaporation of solvent, the product was azeotroped withbenzene (5 mL×2) to give a white powder (0.408 g, 69%): [α]²⁵_(D)+113.54 (c 4.02, CH₂Cl₂); FTIR (CH₂Cl₂ cast) 3386, 3054, 2970, 1602cm⁻¹;¹H NMR (300 MHz, CDCl₃) δ 1.56 (br s, 2H), 1.68-1.78 (m, 2H),2.00-2.30 (m, 16H), 2.38 (dd, J=10.25, 6.3 Hz, 2H), 2.83 (br s, 2H),3.24 (br d, J=12 Hz, 2H), 4.03 (dd, J=9.3, 2.9 Hz, 2H), 6.63 (s, 2H),6.98-7.28 (m, 12H), 7.54 (br s, 2H), 7.92 (br s, 2H); ¹³C NMR (75.5 MHz,CDCl₃) δ 20.17, 20.70, 21.23, 21.33, 21.99, 22.11, 22.65, 22.74, 24.97,25.06, 30.75, 55.19, 58.13, 70.50, 81.52, 123.93, 124.40, 125.78,127.28, 127.33, 127.47, 128.25, 129.24, 129.53, 132.42, 141.85, 143.22,152.61.

[0179] Ligand 1d was prepared in a similar manner by reaction ofN-benzyl-(S)-proline methyl ester (5) with naphthyl magnesium bromide,followed by deprotection of the amine and reaction with2,6-bis(bromomethyl)_(p)-cresol (3).

Example 8 Synthesis of Ligand 1 g

[0180]

[0181] A solution of n-BuLi (1.55 M in hexane, 8.3 mL, 12.8 mmol) wasadded to a solution of furan (1. 12 mL, 15.4 mmol) in THF (20 mL) at 0°C., and the mixture was stirred at 40° C. for 3 h. A solution ofcompound 4 (500 mg, 1.28 mmol) in THF (5 mL) was added to the reactionmixture at 0° C., and the mixture was stirred at room temperature for 1day. Sat. NH₄Cl was added to the reaction mixture, and the mixture wasextracted with ether. The organic layer was washed with brine and driedover magnesium sulfate. Evaporation of the solvent under reducedpressure and purification of the residue by silica gel columnchromatography (pet:AcOEt, 2:1) afforded 1g (710 mg, 1.19 mmol, 93%). IR(neat) ν cm⁻¹; 3385, 2971, 2823, 2810, 1612, 1480, 1381, 1150, 1007,809. ¹H NMR (300 MHz, CDCl₃) d; 7.48 (s, 2H), 7.43 (s, 2H), 6.73 (s,2H), 6.47 (bs, 4H), 6.35 (bs, 4H), 3.90 (d, J=12.7 Hz, 2H), 3.69 (dd,J=6.8, 6.4 Hz, 2H), 3.38 (d, J=12.7 Hz, 2H), 2.72 (ddd, J=9.3, 6.6, 2.9Hz, 2H), 2.30 (dt, J=9.8, 6.4 Hz, 2H), 2.20 (s, 3H), 1.94-1.84 (m, 4H),1.62-1.50 (m, 2H), 1.20-1.04 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) d; 155.7,155.2, 153.3, 142.2, 141.9, 128.9, 127.0, 124.3, 110.4, 110.3, 107.9,107.5, 74.8, 70.2, 58.6, 54.6, 27.9, 24.0, 20.4. HRMS. Calcd forC₃₅H₃₉N₂O₇ (M⁺+H) 599.2757, found 599.2770.

Example 9 Synthesis of Ligand 1 h

[0182]

[0183] A solution of p-bromoanisol (1.93 g, 1.3 mL, 10.3 mmol) in THF (2mL) was added to a suspension of magnesium (311 mg, 12.8 mmol) in THF (2mL) at r.t., and the and the mixture was stirred with refluxing for 30min. A solution of compound 4 (500 mg, 1.28 mmol) in THF (4 mL) wasadded to the mixture, and the mixture was stirred for 18 h. Sat. NH₄Clwas added to the reaction mixture, and the mixture was extracted withether. The organic layer was washed with brine and dried over magnesiumsulfate. Evaporation of the solvent under reduced pressure andpurification of the residue by silica gel column chromatography(pet:AcOEt, 2:1-1:1-AcOEt only) afforded 1 h (373 mg, 0.492 mmol, 38%).¹H NMR (300 MHz, CDCl₃) d; 7.57 (d, J=8.8 Hz, 4H), 7.44 (d, J=8.8 Hz,4H), 6.84 (d, J=8.8 Hz, 8H), 6.62 (s, 2H), 3.86 (dd, J=9.0, 4.6 Hz, 2H),3.77 (s, 6H), 3.73 (s, 6H), 3.54 (d, J=12.7 Hz, 2H), 3.24 (d, J=12.7 Hz,2H), 2.82-2.76 (m, 2H), 2.36 (td, J=9.5, 6.3 Hz, 2H), 2.16 (s, 3H),2.05-1.91 (m, 2H), 1.84-1.72 (m, 2H), 1.66-1.52 (m, 2H), 1.50-1.36 (m,2H). ¹³C NMR (75 MHz, CDCl₃) d; 158.0, 157.9, 152.8, 139.5, 139.0,128.9, 127.1, 124.1, 113.5, 113.2, 78.4, 71.3, 57.9, 55.1, 55.0, 54.9,29.6, 24.0, 20.4.

Example 10 Synthesis of Ligand 1j

[0184] A. Synthesis of compound 6 (see de Mendoza el al., Tetrahedron46:671, 1990).

[0185] To a mixture of paraformaldehyde (6 g), acetic acid (25 mL), andconc. H₂SO₄ (11 mL) was added p-nitrophenol (7 g, 50 mmol) at 55° C.,and the mixture was stirred at the same temperature for 2 days. Water(30 mL) was added to the reaction mixture, followed by K₂CO₃ (0.2 mol).The mixture was filtered, and the precipitate was washed with coldwater. Compound 6 was recrystallized from ethanol (10.9 g, 43 mmol,86%). Spectroscopic data was in good accordance with literature values.

[0186] B. Synthesis of 2,6-bis(bromomethyl)4-nitrophenol (see de Mendozaet al., above).

[0187] A mixture of 6 (1 g, 3.95 mmol) and 48% HBr in water (30 mL) wasstirred at reflux for 15 h. The mixture was filtered at roomtemperature, and the precipitate was washed with cold water. Thecrystals were dissolved in CH₂Cl₂, and the mixture was filtered.Concentration of the filtrate under vacuum gave the title compound (820mg, 2.52 mmol, 64%). Spectroscopic data was in good accordance withliterature values.

[0188] C. Synthesis of Ligand 1j.

[0189] To a solution of diphenylprolinol (253 mg, 0.1 mmol) andtriethylamine (0.14 mL, 1 mmol) in CH₂Cl₂ (2 mL) was added a solution of2,6-bis(bromomethyl)₄-nitrophenol, above (148 mg, 0.455 mmol) in CH₂Cl₂(2 mL) at room temperature, and the mixture was stirred at the sametemperature for 24 h. The mixture was concentrated to half volume undervacuum. Purification of the residue by silica gel column chromatography(pet:AcOEt, 3:1) afforded 1j (146 mg, 0.218 mmol, 48%). IR (neat) νcm⁻¹;3383, 3059, 2972, 2870, 195, 4, 1896, 1816, 1595, 1448, 1333, 1286,1095. ¹HNMR (300 MHz, CDCl₃) d; 7.70 (s, 2H), 7.67 (d, J=7.5 Hz, 4H),7.56 (d, J=7.5 Hz, 4H), 7.36-7.09 (m, 12H), 3.99 (dd, J=9.3, 4.9 Hz,2H), 3.40 (d, J=13.4 Hz, 2H), 3.31 (d, J=13.4 Hz, 2H), 2.85 (ddd, J=9.5,6.4, 3.2 Hz, 2H), 2.38 (td, J=9.5, 6.4 Hz, 2H), 2.14-2.00 (m, 2H),1.91-1.79 (m, 2H), 1.74-1.54 (m, 4H).

Example 11 Synthesis of Ligand 1 k

[0190] A. Synthesis of Compound 7,2,6-bis(hydroxymethyl)4-methoxyphenol(see Moran et al., J. Am. Chem. Soc. 74:127, 1952).

[0191] To a suspension of p-methoxyphenol (6.2 g, 50 mmol) in water (40mL) was added 9.2 mL of 37% formaldehyde solution. To this mixture wasadded 1.6 g of calcium oxide with stirring. The mixture was stored inthe dark for 5 days. The mixture was then treated with 4 mL of aceticacid, cooled at 0° C., the mixture was filtered to give compound 7 (4 g,21.7 mmol, 43%). mp. 128° C. (lit. 127-128° C.). IR (KBr) ν cm⁻¹; 3331,2940, 1736, 1612, 1483, 1456, 1381, 1314, 1261, 1208, 1148, 1069. ¹H NMR(300 MHz, acetone-d₆) d; 8.1 (bs, 1H), 6.74 (s, 2H), 4.73 (s, 4H), 4.64(bs, 2H), 3.71 (s, 3H).

[0192] B. Synthesis of Compound 8,2,6-bis(bromomethyl)4-methoxyphenol(see Moran et al., above)

[0193] To a solution of HBr in acetic acid (22 mL) and acetic acid (3mL) was added compound 7 at room temperature, and the mixture wasstirred at the same temperature for 1 h. The mixture was filtered, andthe filtered solid was washed with acetic acid dried under vacuum (2.8g, 9 mmol, 83%). mp. 105° C. (lit. 113-114° C.). IR (KBr) ν cm⁻¹; 3497,2940, 2838, 1617, 1483, 1438, 1333, 1259, 1195, 1159, 1044, 985. ¹H NMR(300 MHz, CDCl₃) δ; 6.83 (s, 2H), 5.21 (s, 1H), 4.53 (s, 4H), 3.77 (s,3H).

[0194] C. Synthesis of Compound 9.

[0195] To a solution of L-proline methyl ester hydrochloride (900 mg,5.43 mmol) and compound 8 (700 mg, 2.26 mmol) in CH₂Cl₂ (20 mL) wasadded triethylamine (1.45 g, 2 mL, 14.3 mmol) at room temperature, andthe mixture was stirred at the same temperature for 3 h. The mixture waspoured onto water and extracted with ether. The organic layer was washedwith brine and dried over magnesium sulfate. Evaporation of the solventunder reduced pressure and purification of the residue by silica gelcolumn chromatography (CHCl₃:MeOH, 10:1) afforded 9 (750 mg, 1.85 mmol,82%). IR (neat) ν cm⁻¹; 3352, 2952, 2836, 1740, 1611, 1479, 1378, 1272,1204, 1054, 862. ¹H NMR (300 MHz, CDCl₃) δ; 6.65 (s, 2H), 4.00 (d,J=13.2 Hz, 2H), 3.72 (s, 3H), 3.70 (s, 6H), 3.63 (d, J=13.2 Hz, 2H),3.31 (dd, J=8.5, 5.9 Hz, 2H), 3.11-3.04 (m, 2H), 2.50-2.41 (m, 2H),2.23-2.09 (m, 2H), 2.00-1.73 (m, 6H). ¹³C NMR (75 MHz, CDCl₃) δ; 174.2,151.8, 149.6, 123.6, 114.4, 64.8, 55.7, 54.3, 52.9, 51.9, 29.4, 23.1.

[0196] D. Synthesis of ligand 1k.

[0197] To a solution of compound 9 (680 mg, 1.68 mmol) in THF (15 mL)was added a solution of phenylmagnesium chloride (2 M in THF, 6.7 mL,13.4 mmol) at room temperature, and the mixture was stirred at the sametemperature for 20 h. Sat. NB₄CI was added to the reaction mixture, andthe mixture was extracted with ether. The organic layer was washed withbrine and dried over magnesium sulfate. Evaporation of the solvent underreduced pressure and purification of the residue by silica gel columnchromatography (CHCl₃:MeOH, 40:1) afforded 1k (650 mg, 0.994 mmol, 59%).IR (neat) ν cm⁻¹; 3384, 3058, 3022, 2973, 2871, 1954, 1887, 1811, 1597,1480, 1449, 1381. ¹H NMR (300 MHz, CDCl₃) δ; 7.68 (d, J=7.3 Hz, 4H),7.55 (d, J=7.3 Hz, 4H), 7.34-7.10 (m, 12H), 6.38 (s, 2H), 3.98 (dd,J=9.3, 4.6 Hz, 2H), 3.69 (s, 3H), 3.36 (d, J=12.7 Hz, 2H), 3.26 (d,J=12.7 Hz, 2H), 2.84 (ddd, J=9.8, 6.3, 3.2 Hz, 2H), 2.41 (td, J=9.8, 6.3Hz, 2H), 2.09-1.95 (m, 2H), 1.86-1.75 (m, 2H), 1.70-1.47 (m, 4H). ¹³CNMR (75 MHz, CDCl₃) δ; 151.6, 148.8, 146.9, 146.3, 128.2, 128.0, 126.6,126.4, 125.9, 125.8, 124.8, 113.6, 78.9, 71.4, 57.7, 55.6, 55.1, 29.6,24.1.

Example 12 Synthesis of Ligand 1 m

[0198] A. Synthesis of compound 10, dimethyl (2-hydroxy-4,6-dimethyl)isophthalate (see Bertz, Synthesis 708, 1980 and Fahmi et al., Helv.Chim. Acta 81:491, 1998).

[0199] To a solution of 2,4-pentanedione (8.7 g, 50 mmol) was added 2.5mL of 2N NaOH and 47.5 mL of water at room temperature, and the mixturewas stirred at the same temperature for 10 min. A solution of dimethylacetonedicarboxylate in MeOH (50 mL) was added to the reaction mixture,and the mixture was stirred at room temperature for 24 h. The mixturewas filtered, and the solid was washed with water and dried under vacuum(10, 10.2 g, 42.9 mmol, 86%). Spectroscopic data was in good accordancewith literature values.

[0200] B. Synthesis of compound 11,2.6-bis(hydroxymethyl)-3,5-dimethylphenol. (See Fitzgerald, J. Appl.Chem. 289, 1955.)

[0201] To a suspension of LiAlH₄ (3.7 g, 97.1 mmol) in THF (80 mL) wasadded a solution of 10 (7 g, 29.4 mmol) in THF (40 mL) at roomtemperature, and the mixture was stirred at 50° C. overnight. 1N HCl (80mL) was added carefully to the mixture, and the mixture was extractedwith AcOEt. The aqueous layer was extracted with AcOEt:THF. The combinedorganic layer was washed with brine and dried over magnesium sulfate.Evaporation of the solvent under reduced pressure and purification ofthe residue by recrystallization from AcOEt afforded 11 (4.9 g, 26.9mmol, 92%). mp. 145° C. (lit. 142-144° C.). IR (KBr) ν cm⁻¹; 3458, 3222,3082, 2905, 1627, 1576, 1460, 1304, 1083, 1033, 1004, 986. ¹H NMR (300MHz, CDCl₃) d; 9.19 (s, 1H), 6.46 (s, 1H), 4.76 (s, 4H), 4.40 (s, 2H),2.21 (s, 6H).

[0202] C. Synthesis of Compound 12, 2,6-bis(bromomethyl)4-methoxyphenol.

[0203] To a solution of compound 11 (2.1 g, 11.5 mmol) in ether (20 mL)was added 48% aqueous HBr (10 mL) at room temperature, and the mixturewas stirred at the same temperature for 20 min. The mixture was pouredonto water and extracted with ether. The organic layer was washed withwater and brine and dried over magnesium sulfate. Evaporation of thesolvent under reduced pressure gave almost pure 12 (3.4 g, 11.0 mmol,96%). mp. 119° C. 1R (KBr) ν cm⁻¹; 3538, 3472, 2926, 1619, 1572, 1448,1306, 1254, 1208, 1148, 1040, 969. ¹H NMR (300 MHz, CDCl₃) 5; 6.68 (s,1H), 5.41 (s, 1H), 4.62 (s, 4H), 2.36 (s, 6H). ¹³C NMR (75 MHz, CDCl₃)δ; 153.5, 138.8, 125.4, 121.4, 26.6, 18.9.

[0204] D. Synthesis of Compound 13.

[0205] To a solution of L-proline methyl ester hydrochloride (4.6 g, 28mmol) and triethylamine (6.7 g, 9.2 mL, 66 mmol) in CH₂Cl₂ (60 mL) wasadded a solution of 12 (3.4 g, 11 mmol) in CH₂Cl₂ (40 mL) at roomtemperature, and the mixture was stirred at the same temperature for 18h. The mixture was concentrated to half volume under vacuum and theresidue purified by silica gel column chromatography (pet:AcOEt, 2:1) toafford 13 (2.3 g, 5.69 mmol, 52%). IR (neat) ν cm⁻¹; 2951, 2851, 1732,1622, 1574, 1455, 1372, 1311, 1203, 1133, 1073, 1039. ¹HNMR (300 MHz,CDCl₃) δ; 10.6(s, 1H), 6.46 (s, 1H), 3.86 (d, J=13.0 Hz, 2H), 3.78 (d,J=13.0 Hz, 2H), 3.68 (s, 6H), 3.30 (dd, J=8.8, 6.1 Hz, 2H), 3.05-2.97(m, 2H), 2.46 (q, J=8.3 Hz, 2H), 2.25 (s, 6H), 2.22-1.72 (m, 8H). ¹³CNMR (75 MHz, CDCl₃) δ; 174.5, 156.6, 136.5, 122.9, 119.4, 65.1, 52.7,51.8, 50.1, 29.6, 23.2, 19.4. HRMS. Calcd for C₂₂H₃₂N₂O₅ (M⁺) 404.2311,found 404.2305.

[0206] E. Synthesis of Ligand 1 m.

[0207] To a solution of compound 13 (2.25 g, 5.57 mmol) in THF (10 mL)was added a solution of phenylmagnesium chloride (2 M in THF, 28 mL,55.7 mmol) at room temperature, and the mixture was stirred at the sametemperature for 2 days. Sat. NH₄Cl was added to the reaction mixture,and the mixture was extracted with ether. The organic layer was washedwith brine and dried over magnesium sulfate. Evaporation of the solventunder reduced pressure and purification of the residue by silica gelcolumn chromatography (pet:AcOEt, 4:1-2:1) afforded 1m (2.5 g, 3.83mmol, 69%). [α]_(D) ² ^(₆) +26.2 (c 1.62, CHCl₃). IR (neat) ν cm⁻¹;3356, 3059, 3029, 2967, 2870, 1686, 1598, 1573, 1493, 1449, 1374, 1311.¹H NMR (300 MHz, CDCl₃) δ; 7.55 (d, J=8.1 Hz, 4H), 7.60 (d, J=80 Hz,4H), 7.35-7.09 (m, 12H), 6.32 (s, 1H), 4.01 (dd, J=9.3, 4.9 Hz, 2H),3.53 (d, J=12.7 Hz, 2H), 3.19 (d, J=12.7 Hz, 2H), 2.79-2.71 (m, 2H),2.45 (td, J=9.5, 6.3 Hz, 2H), 2.10-1.94 (m, 2H), 2.05 (s, 6H), 1.85-1.74(m, 2H), 1.68-1.48 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) 5; 156.1, 147.1,146.7, 135.6, 128.1, 128.0, 126.6, 126.3, 125.9, 125.7, 122.6, 120.2,78.7, 71.7, 54.3, 53.3, 29.7, 23.9, 19.7. MS(SIMS) 653.4 (M⁺+1).

Example 13 Synthesis of Ligand 1n

[0208]

[0209] The dibromide 2,6-bis(bromomethyl)-4-chlorophenol (0.23 g, 0.747mmol) was added in one portion to a stirred and cooled (0° C.) solutionof (S)-diphenylprolinol (0.397 g, 1.56 mmol) and K₂CO₃ (0.86 g, 6.24mmol) in dry DMF (3 mL). After the addition, the solution was brought toroom temperature and stirring was continued for 12 h. The mixture waspartitioned with Et₂O (20 mL) and H₂O (10 mL). The aqueous phase wasextracted with Et₂O (10 mL x 2), and the combined organic phases werewashed with water and brine, dried (MgSO₄), and concentrated. Theresidue was purified over silica gel using 5 to 105 EtOAc-pet ether togive in (0.352 g, 72%) as a powder: [α]²⁵ _(D)+69.64 (c 1.82, CH₂Cl₂);FTIR (CH₂Cl₂ cast) 3418, 3028, 2965, 1599 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)δ 1.46-1.70 (m, 4H), 1.72-1.88 (m, 2H), 1.94-2.08 (m, 2H), 2.36 (dd,J=16.2, 9.3 Hz, 2H), 2.78-2.88 (m, 2H), 3.20 (d, J=13.2, 2H), 3.36 (d,J=13.2 Hz, 2H), 3.96 (dd, J=8.8, 4.4 Hz, 2H), 6.75 (s, 2H), 7.10-7.36(m, 12H), 7.56 (d, J=7.3 Hz, 4H), 7.66 (d, J=7.3 Hz, 4H); ¹³C NMR (75.5MHz, CDCl₃) δ 24.06, 29.55, 5.11, 57.26, 71.31, 78.91, 122.61, 125.81,125.89, 125.92, 126.49, 126.65, 127.54, 128.04, 128.20, 146.29, 146.75,153.65.

Example 14 Enantioselective Aldol Reactions of Aryl Methyl Ketones(Table 1) Standard Procedure

[0210] A. Preparation of Catalyst (Ligand:Zinc 1:2).

[0211] Under an argon atmosphere, a solution of diethylzinc (1 M inhexane, 0.2 mL, 0.2 mmol) was added to a solution of 1a (64 mg, 0.1mmol) in THF (1 mL) at ambient temperature, and the solution was stirredat the same temperature for 30 min.

[0212] B. Aldol Reaction.

[0213] Under an argon atmosphere, 0.25 mL of the catalyst solutionprepared above (ca. 0.021 mmol) was added to a suspension of powdered 4Amolecular sieves (100 mg, dried at 150° C. under vacuum overnight),aldehyde (0.5 mmol), acetophenone (600 mg, 0.6 mL, 5 mmol), andtriphenylphosphine sulfide (22.1 mg, 0.075 mmol) in THF (0.8 mL) at 5°C. The mixture was stirred at the same temperature for 15 h-2d. Thereaction mixture was poured onto 1N HCl to remove the ligand, and themixture was extracted with ether. The organic layer was washed withbrine and dried over magnesium sulfate. Evaporation of the solvent underreduced pressure and purification of the residue by silica gel columnchromatography afforded the product.

[0214] Characterizating Data for Products in Table 1

[0215] Entry 1

[0216] Previously reported in Narasaka et al., Chem. Lett. 1399 (1984).

[0217] [α]_(D) ²⁵+31.9 (c 0.75, CHCl₃). (56% ee).

[0218] Entry 2

[0219] (68% ee). [α]_(D) ²⁵+55.5 (c 4.07, CHCl₃). IR (neat) ν cm⁻¹;3456, 2957, 1680, 1598, 1581, 1450, 1367, 1211, 1072, 1041. ¹H NMR (300MHz, CDCl₃) δ; 7.95 (d, J=7.3 Hz, 2H), 7.58 (t, J=7.3 Hz, 1H), 7.46 (t,J=7.3 Hz, 2H), 4.36-4.26 (m, 1H), 3.24 (d, J=3.2 Hz, 1H), 3.15 (dd,J=17.6, 2.7 Hz, 1H), 3.03 (dd, J=17.6, 8.6 Hz, 1H), 1.94-1.80 (m, 1H),1.59 (ddd, J=13.9, 9.0, 5.4 Hz, 1H), 1.25 (ddd, J=13.9, 8.8, 4.4 Hz,1H), 0.95 (d, J=6.6 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃) δ; 201.0, 136.8,133.5, 128.6, 128.0, 65.8, 45.6, 45.5, 24.4, 23.3, 22.0. Anal. Calcd forC₁₃H₁₈O₂: C, 75.69; H, 8.79. Found: C, 75.48; H, 8.60.

[0220] Entry 3

[0221] Previously reported in Veeraraghavan Ramachandran et al., Tet.Lett. 37:4911 (1996).

[0222] [α]_(D) ²⁵+77.6 (c 1.43, CHCl₃). (97% ee).

[0223] Entry 4

[0224] Previously reported in Narasaka et al, Chem. Lett 1399 (1984).

[0225] [α]D²⁵+63.7 (c 1.54, CHCl₃). (98% ee)

[0226] Entry 5

[0227] (99% ee). mp 128° C. (from ether). [α]_(D) ²³+4.6 (c 1.17,CHCl₃). IR (KBr) νcm⁻¹; 3528, 1659, 1596, 1494, 1448, 1405, 1328, 1214,1090, 1002. ¹H NMR (300 MHz, CDCl₃) δ; 7.89-7.19 (m, 15H), 5.13-5.04 (m,1H), 4.09 (d, J=9.3 Hz, 1H), 3.16 (dd, J=17.3, 7.8 Hz, 1H), 3.12 (bs,1H), 3.08 (dd, J=17.3, 3.4 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ; 200.4,142.0, 141.4, 136.7, 133.4, 128.8, 128.7, 128.6, 128.5, 128.3, 128.1,126.8, 126.7, 70.0., 57.7, 43.5. Anal. Calcd for C₂₂H₂₀O₂: C, 83.52; H,6.37. Found: C, 83.42; H, 6.22.

[0228] Entry 6

[0229] Previously reported in Meyers and Walkup, Tetrahedron 41:5089(1985).

[0230] Major isomer 94% ee, minor isomer 98% ee.

[0231] Entry 7

[0232] (93% ee). [α]_(D) ²⁵+40.6 (c 1.9, CHCl₃). IR (neat) ν cm⁻¹; 3498,2956, 2929, 2857, 1679, 1598, 1581, 1472, 1448, 1252, 1095, 837. ¹H NMR(300 MHz, CDCl₃) δ; 7.97 (d, J=8.1 Hz, 2H), 7.55 (t, J=8.1 Hz, 1H), 7.45(t, J=8.1 Hz, 2H), 4.20 (ddd, J=8.6, 3.9, 3.2 Hz, 1H), 3.65 (d, J=3.2Hz, 1H), 3.52 (s, 2H), 3.14 (dd, J=16.4, 8.6 Hz, 1H), 3.07 (dd, J=16.4,3.9 Hz, 1H), 0.98 (s, 3H), 0.90 (s, 12H), 0.07 (s, 6H). ¹³C NMR (75 MHz,CDCl₃) δ; 200.7, 137.3, 133.1, 128.5, 128.2, 73.9, 71.6, 40.8, 38.6,25.8, 21.7, 19.5, 18.2, −5.6, −5.7. Anal. Calcd for C₁₉H₃₂O₃Si: C,67.81; H, 9.58. Found: C, 67.96; H, 9.38.

[0233] Entry 8

[0234] Previously reported in Loh et al., Tetrahedron 55:10789 (1999).

[0235] [α]_(D) ²⁵+72.2 (c 1.2, CHCl₃). (97% ee).

[0236] Entry 9

[0237] (97% ee). [α]_(D) ²⁵+3.4 (c 1.06, CHCl₃). IR (neat) ν cm⁻¹; 3494,2961, 1667, 1598, 1579, 1486, 1467, 1438, 1297, 1245, 1025, 758. ¹H NMR(300 MHz, CDCl₃) δ; 7.70 (dd, J=7.8, 1.7 Hz, 1H), 7.47 (dt, J=8.8, 1.7Hz, 1H), 7.03-6.90 (m, 2H), 3.96-3.80 (m, 1H), 3.90 (s, 3H), 3.27 (dd,J=17.6, 2.2 Hz, 1H), 3.23 (s, 1H), 2.97 (dd, J=17.6, 9.8 Hz, 1H),1.84-1.70 (m, 1H), 0.98 (d, J=7.8 Hz, 3H), 0.95 (d, J=7.8 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ; 203.6, 158.7, 133.9, 130.2, 128.0, 120.7, 111.6,72.7, 55.5, 47.3, 33.1, 18.4, 17.9. Anal. Calcd for C₁₃H₁₈03: C, 70.25;H, 8.16. Found: C, 70.40; 1, 7.96.

[0238] Entry 10

[0239] (98% ee). mp 49° C. (from ether). [α]_(D) ²⁵+49.7 (c 3.35, CHCl₃)IR (KBr) ν cm; 3482, 2966, 1676, 1601, 1576, 1509, 1422, 1261, 1218,1173, 1031 ¹H NMR (300 MHz, CDCl₃) δ; 7.92 (d, J=9.0 Hz, 2H), 6.91 (d,J=9.0 Hz, 2H), 3.99-3.91 (m, 1H), 3.85 (s, 3H), 3.37 (d, J=3.2 Hz, 1H),3.11 (dd, J=17.3, 2.4 Hz, 1H), 2.94 (dd, J=17.3, 9.5 Hz, 1H), 1.83-1.72(m, 1H), 0.99 (d, J=6.8 Hz, 3H),0.95 (d, J=6.8 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ; 199.8, 163.7, 130.3, 129.9, 113.7, 72.4, 55.4, 41.3, 33.1,185, 17.8.

[0240] Anal. Calcd for C₁₃H₁₈O₃: C, 70.25; H, 8.16. Found: C, 70.40; H,7.95.

[0241] Entry 11

[0242] (96% ee). mp 61-64° C. (from ether). [α]_(D) ²⁵+53.7 (c 1.33,CHCl₃) IR (KBr) ν cm⁻¹; 3518, 2949, 1665, 1626, 1470, 1373, 1213, 1184,1122, 1008. ¹H NMR (300 MHz, CDCl₃) δ; 8.45 (s, 1H), 8.01 (dd, J=8.5,1.7 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.90-7.84 (m, 2H), 7.63-7.52 (m,2H), 4.10-4.02 (m, 1H), 3.32 (d, J=3.4 Hz, 1H), 3.29 (dd, J=17.3, 2.4Hz, 1H), 3.16 (dd, J=17.3, 9.3 Hz, 1H), 1.91-1.79 (m, 1H), 1.06 (d,J=6.3 Hz, 3H), 1.03 (d, J=6.3 Hz, 3H). ³C NMR (75 MHz, CDCl₃) δ; 201.2,135.7, 134.2, 132.4, 129.9, 129.6, 128.6, 128.5, 127.7, 126.8, 123.5,72.4, 42.0, 33.1, 18.6, 17.9. Anal. Calcd for C₁ ₆ H₁₈O₂: C, 79.31; H,7.49. Found: C, 79.57; H, 7.23.

Example 15 Enantioselective Aldol Reactions of Acetone (Table 2):Standard Procedure.

[0243] Catalyst generation: Under an argon atmosphere, a solution ofdiethylzinc (1M in hexanes, 0.4 ml, 0.4 mmol) was added to the solutionof ligand 1 a (128 mg, 0.2 mmol) or 1m (130 mg, 0.2 mmol) in THF (2 ml)at r.t. After stirring for 30 min, with the evolution of ethane gas, theresulting solution (ca 0.1 M) was used as catalyst for the aldolreaction.

[0244] Aldol reaction: To a suspension of aldehyde (0.5 mmol), powderedmolecular sieves (100 mg, dried at ca. 150° C. under vacuum overnight)and acetone (0.5 ml, 6.8 mmol) in THF (0.8 ml) was added the solution ofcatalyst (0.025 mmol for 5% catalyst, 0.05 mmol for 10% catalyst) at 0°C., and the mixture was stirred at 5° C. for 2 d. The resulting mixturewas poured onto 1N HCl and extracted with ether. After normal workup,the crude product was purified by silica gel chromatography using amixture of petroleum ether and ethyl acetate as eluent.

[0245] Characterizating Data for Products in Table 2.

[0246] Entry 1: (S)-4-Cyclohexyl-4-hydroxybutan-2-one

[0247] Previously reported in Silverman et al., J. Org. Chem. 52:180,1987.

[0248] [α]_(D) ²+50.1 (c 1.5, CHCl₃) ee=87% (lit. [α]_(D) ²⁵+52 (c 1.1,CCl₄)). IR (neat) ν cm⁻¹; 3456, 2925, 2853, 2361, 1712, 1450, 1418,1360, 1165. ¹H NMR (300 MHz, CDCl₃) δ; 3.80 (bs, 1H), 2.90 (s, 1H), 2.63(dd, J 17.3, 27 Hz, 1H), 2.53 (dd, J=17.3, 9.0 Hz, 1H), 2.18 (s, 3H),1.86-0.92 (m, 11H). ¹³C NMR (75 MHz, CDCl₃) δ; 210.5, 71.6, 47.1, 42.9,30.9, 28.8, 28.2, 26.4, 26.1, 26.0.

[0249] Entry 2: (S)-4-hydroxy-5-methylhexan-2-one

[0250] Previously reported in List, B. et al., J. Am. Chem. Soc. 122,2395 (2000); Barbas, C. F.(III) et al., J. Am. Chem. Soc. 112, 2013(1990).

[0251] [α]_(D) ²⁵+53.7 (c 1.5, CHCl₃) ee=91% (lit. [α]_(D) ²⁵+61.7 (c0.6, CHCl₃)). ¹H NMR (300 MHz, CDCl₃) δ; 3.84-3.75 (m, 1H), 2.95 (bs,1H), 2.61 (dd, J=17.6, 3.0 Hz, 1H), 2.51 (dd, J=17.6, 9.0 Hz, 1H), 2.18(s, 3H), 1.72-1.61 (m, 1H), 0.92 (d, J=7.4 Hz, 3H), 0.89 (d, J=7.1 Hz,1H). ¹³C NMR (75 MHz, CDCl₃) δ; 210.4, 72.1, 46.9, 33.0, 30.8, 18.3,17.7.

[0252] Entry 3: (S)-5,5-dimethyl-4-hydroxyhexan-2-one

[0253] Previously reported in Narasaka, K. et al., Chem. Lett. 1399(1984).

[0254] [α]_(D) ²⁵+49.0 (c 0.8, CHCl₃) ee=86% (lit. [α]_(D) ²⁵+43.9 (c0.8, CHCl₃) ee=86%, lit. [α]D²⁵+82.2 (c 0.6, CHCl₃) ee=83%).

[0255] Entry 4: 5,5-diphenyl-4-hydroxypentan-2-one

[0256] ee=87%. [α]_(D) ²¹⁵+11.43 (c 0.9, CHCl₃). IR (neat) ν cm⁻¹; 3520(OH), 1704 (C═O). ¹H-NMR (300 MHz, CDCl₃) δ; 7.41-7.19 (m, 10H), 4.86(m, 1H), 3.92 (d, J=9.0 Hz, 1H), 3.66 (m, 1H), 2.50 (m, 2H), 2.02 (s,3H). ¹³C-NMR (75 MHz, CDCl₃) δ; 209.3, 141.9, 141.2, 128.8, 128.7,128.3, 127.2, 127.0, 126.8, 69.8, 57.6, 48.4, 30.9. MS (SIMS) M⁺=254.3Anal. calcd for C₁₇H₁₈O₂: C, 80.28; H, 7.13. Found C, 80.12; H, 7.14.

[0257] Entry 5: 4-hydroxy-6-methylheptan-2-one

[0258] ee=84%. [α]_(D) ^(215+47.04) (c 0.7, CHCl₃). IR (neat) ν cm⁻¹;3410 (OH), 1712 (C═O). ¹H-NMR (300 MHz, C₆D₆) 6; 3.75 (m, 1H), 2.22 (m,2H), 2.17 (s, 3H), 2.11 (M, 1H), 1.21 (m, 2H), 0.99 (d, J=6.3 Hz, 6H).³C-NMR (75 MHz, C6D₆) 6; 195.9, 71.7, 48.5, 38.2, 30.4, 20.7, 17.5. MS(SIMS) M⁺=144.2. Anal. calcd for C₈H₁₆O₂: C, 66.63; H, 11.18. Found C,66.33; H, 11.08

[0259] Entry 6: (5)-4-hydroxy-6-phenylhexan-2-one

[0260] Previously reported in Carreira, E. M. et al., J. Am. Chem. Soc.117, 3649 (1995).

[0261] [α]_(D) ²⁵19.9 (c 0.7, CHCl₃) ee=84% (lit. [α]_(D) ²⁵+20.6 (c1.0, CHCl₃)).

[0262] Entry 7: (S)-4-hydroxyheptan-2-one

[0263] Previously reported in Paterson et al., Tetrahedron Lett. 30:997(1989).

[0264] [α]_(D) ^(25+42.3) (c 5.0, CHCl₃) ee=84% (lit. [α]_(D) ²⁵+³5.1 (c2.1, CHCl₃) ee=58%).

[0265] Entry 8: (S)-4-hydroxy-4-phenylbutan-2-one

[0266] Previously reported in Paterson et al, Tetrahedron 46, 4663(1990).

[0267] [α]_(D) ²⁵+0.8 (c 1.0, CHCl₃) ee=79% (lit. [α]_(D) ²⁰+0.9 (c10.3, CHCl₃) ee=78%).

[0268] Entry 9: 4-hydroxy-4-(4-nitrophenyl)butan-2-one

[0269] Previously reported in Grayson, D. H. et al., J. Chem. Soc.,Perkin 12137 (1986).

[0270] Mp 62° C. (lit. 60-62° C.). ee=79%. [α]_(D) ²⁰+36.8 (c 1.7,CHCl₃). IR (neat) ν cm⁻¹; 3493 (OH), 1710 (C═O). ¹H-NMR (300 MHz, CDCl₃)δ; 8.20 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 5.20 (dd, J=7.3, 4.7Hz, 1H), 4.77 (bs, 1H), 2.80 (m, 2H), 2.16 (s, 3H). ¹³C-NMR (75 MHz,CDCl₃) δ; 208.6, 149.85, 140.2, 128.8, 124.2, 68.9, 51.5, 30.8. MS(SIMS) M⁺=209.2. Anal. calcd for C₁₀H₁₁NO₄: C, 57.41; H, 5.30, N, 6.70.Found C, 57.29; H, 5.34; N, 6.72.

Example 16 Enantioselective Aldol Reactions of Methyl Vinyl Ketone(Table 3) Standard Procedure

[0271] The procedure essentially as described for Table 2 (Example 15)was followed for the reaction of cyclohexanecarboxaldehyde (56 mg, 61μL, 0.5 mmol) and MVK (1.5 mL), at a temperature of 0° C., replacing theadditive Ph₃PS with those shown in Table 3. For preparation of catalyst,equimolar amounts of ligand and metal complex were used.

[0272] The product of entry 6 was purified by silica gel columnchromatography (pet:ether, 1:1) to give 5-hydroxy-5-cyclohexylpenten-3-one, 58 mg, 0.324 mmol, 65%, 94% ee. t, =23.76 min and 24.23min (major enantiomer), (Chiral GC, CycloSil-B, 150° C.). IR (neat) νcm⁻¹; 3462, 2925, 2853, 1682, 1614, 1450, 1403, 1189, 989. ¹H NMR (300MHz, CDCl₃) δ; 636 (dd, J=17.6, 10.0 Hz, 1H), 6.25 (dd, J=17.6, 15 Hz,1H), 5.89 (dd, J=100, 1.5 Hz, 1H), 3.90-3.82 (m, 1H), 2.97 (d, J=3.7 Hz,1H), 2.80 (dd, J=17.3, 2.7 Hz, 1H), 2.69 (dd, J=17.3, 9.3 Hz, 1H),1.90-1.00 (m, 11H). ¹³C NMR (75 MHz, CDCl₃) δ; 201.9, 136.8, 129.0,71.6, 43.0, 42.9, 28.9, 28.3, 26.4, 26.2, 26.1.

Example 17 Enantioselective Aldol Reactions of Acetone and MVK usingVarious Ligands (Table 4): Standard Procedure.

[0273] Under an argon atmosphere, a solution of diethylzinc (0.1 mmol)was added to a solution of indicated ligand (0. 1 mmol) in toluene (1mL) at ambient temperature; the solution was stirred for 30 minutes.This solution (0.5 mL) was added under argon to a solution ofcyclohexanecarboxaldehyde (56 mg, 62 L, 0.5 mmol), acetone or MVK (0.5to 1.5 mL), and the indicated additive(s), at the indicated temperature,and the mixture was stirred at same temperature for 15 h-4 days, asindicated. The reaction mixture was poured onto 1N HCl, and the mixturewas extracted with ether. The organic layer was washed with brine anddried over magnesium sulfate. Solvent was removed under reduced pressureand the residue purified by silica gel column chromatography (pet:ether,1:1)

Example 18 Enantioselective Aldol Reactions of α-Hydroxyacetophenone(Table 6) Standard Procedure.

[0274] Under an argon atmosphere, a solution of diethylzinc (1M inhexane, 0.2 mL, 0.2 mmol) was added to a solution of 1a (64 mg, 0.1mmol) in THF (1 mL) at ambient temperature, and the solution was stirredat the same temperature for 30 min.

[0275] This solution (0.25 mL) was added to a suspension of powdered 4Amolecular sieves (100 mg, dried at 150° C. under vacuum overnight),aldehyde (0.5 mmol), and hydroxymethyl aryl ketone (0.75 mmol) in THF(1.5 mL) at −35° C. The mixture was stirred at the same temperature for1-2d. The reaction mixture was poured onto 1N HCl and extracted withether. The organic layer was washed with brine and dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuepurified by silica gel column chromatography.

[0276] Characterizating Data for Products in Table 6

[0277] All compounds were purified by silica gel column chromatography,eluting with PE:AcOEt or PE:ether.

[0278] Entry 1

[0279] Major diastereomer (less polar isomer):

[0280] t_(r)=7.44 min (major enantiomer) and 10.43 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=90:10, 1 mL/min). mp 77° C. [α]_(D)²⁵−2.76 (c 3.0, CHCl₃, 91% ee). IR (KBr) ν cm⁻¹; 3457, 3060, 2920, 2850,1682, 1599, 1578, 1449, 1395, 1257, 1119, 1037. ¹H NMR (300 MHz, CDCl₃)δ; 7.86 (d, J=7.1 Hz, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.50 (t, J=7.1 Hz,2H), 5.22 (dd, J=5.1, 1.2 Hz, 1H), 3.99 (d, J=5.1 Hz, 1H), 3.58 (td,J=9.0, 1.2 Hz, 1H), 2.08-0.88 (m, 11H), 1.88 (d, J=10.3 Hz, 1H). ¹³C NMR(75 MHz, CDCl₃) δ; 200.8, 133.9, 133.6, 128.9, 128.4, 77.0, 73.2, 41.3,29.4, 29.3, 26.3, 25.9, 25.8. Anal. Calcd for C₁₅H2₀O₃: C, 72.55; H,8.12. Found: C, 72.74; H, 8.05.

[0281] Minor diastereomer (more polar isomer):

[0282] t_(r)=8.54 min and 9.77 min, (Chiralcel OD, λ=254 nm,heptane:isopropanol=90:10, 1 mL/min).

[0283] Entry 2.

[0284] Major diastereomer (less polar isomer):

[0285] t_(r)=6.15 min (major enantiomer) and 7.81 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=80:20, 1 mL/min). mp 86° C. [α]_(D)²⁴−40.2 (c 1.32, CHCl₃, 86% ee). IR (KBr) ν cm⁻¹; 3445, 2962, 2876,1688, 1597, 1578, 1472, 1449, 1410, 1310, 1265, 1138. ¹H NMR (300 MHz,CDCl₃) δ; 7.86 (d, J=7.3 Hz, 2H), 7.61 (t, J=7.3 Hz, 1H), 7.49 (t, J=7.8Hz, 2H), 5.20 (d, J=3.4 Hz, 1H), 4.01 (d, J=4.6 Hz, 1H), 3.51 (t, J=9.3Hz, 1H), 2.06 (d, J=10.5 Hz, 1H), 2.03-1.91 (m, 1H), 1.11 (d, J=6.6 Hz,3H), 1.02 (d, J=6.8 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ; 200.7, 133.9,133.6, 128.9, 128.4, 78.0, 73.6, 32.1, 19.2, 19.1. Anal. Calcd forC₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C, 69.36; H, 7.59.

[0286] Minor diastereomer (more polar isomer):

[0287] t_(r)=6.84 min (major enantiomer) and 7.25 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=80:20, 1 mL/min).

[0288] Entry 3.

[0289] Major diastereomer (less polar isomer):

[0290] t_(r)=12.50 min (major enantiomer) and 22.12 min, (Chiralcel AD,λ=254 nm, heptane:isopropanol,=80:20, 1 mL/min). mp 161-166° C. [α]_(D)²⁴-411 (c 1.02, CHCl₃, 81% ee). IR (KBr) ν cm⁻¹; 3552, 3492, 3057, 3030,2921, 1681, 1597, 1579, 1451, 1271, 1090, 979. ¹H NMR (300 MHz, CDCl₃)δ; 7.67-7.14 (m, 15H), 4.91 (bd, J=2.7 Hz, 1H), 4.71 (dd, J=10.5, 8.1Hz, 1H), 4.44 (d, J=10.5 Hz, 1H), 4.09 (bd, J=4.1 Hz, 1H), 2.17 (d,J=8.1 Hz, 1H), 1.02 (d, J=6.8 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ; 200.0,141.5, 140.7, 133.9, 133.5, 129.0, 128.8, 128.6, 128.5, 128.44, 128.40,127.2, 126.7, 74.5, 72.9, 55.3. Anal. Calcd for C₂₂H2₀O₃: C, 79.50; H,6.06. Found: C, 79.66; H, 5.97.

[0291] Minor diastereomer (more polar isomer):

[0292] t_(r)=11.33 min (major enantiomer) and 14.08 min, (Chiralcel AD,λ=254 nm, heptane:isopropanol=80:20, 1 mL/min).

[0293] Entry 4a.

[0294] Major diastereomer (less polar isomer):

[0295] t_(r)=7.69 min (major enantiomer) and 9.48 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=90:10, 1 mL/min). mp 60-61° C. [α] D²⁵15.9 (c 1.58, CHCl₃, 88% ee). IR (KBr) ν cm⁻¹; 3333, 2951, 2867, 1684,1598, 1580, 1470, 1450, 1319, 1249, 1148, 1104. ¹H NMR (300 MHz, CDCl₃)5; 7.88 (d, J=7.3 Hz, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.50 (t, J=7.3 Hz,2H), 4.95 (bs, 1H), 4.01 (bs, 2H), 2.01 (bs, 1H), 1.88-1.74 (m, 1H),1.67 (ddd, J=13.7, 8.8, 6.1 Hz, 1H), 1.49 (ddd, J=13.7, 7.8, 4.9 Hz,1H), 0.96 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ; 200.3, 133.9, 133.8, 128.9, 128.4, 75.9, 71.0, 43.6, 24.5,23.2, 22.1. Anal. Calcd for C₁₃H18O₃: C, 70.25; H, 8.16. Found: C,70.45; H, 7.95.

[0296] Minor diastereomer (more polar isomer):

[0297] t₁=14.02 min (major enantiomer) and 14.90 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=95:15, 1 mL/min). ¹H NMR (300 MHz, CDCl₃)δ; 7.94 (d, J=7.3 Hz, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.51 (t, J=7.3 Hz,2H), 5.24 (bs, 1H), 4.02 (bd, J=10.3 Hz, 1H), 3.85 (bd, J=6.1 Hz, 1H),2.24 (bs, 1H), 1.78-1.64 (m, 1H), 1.40 (ddd, J=14.2, 10.7, 4.9 Hz, 1H),0.81 (d, J=6.8 Hz, 3H), 0.75 (ddd, J=14.2, 9.8, 2.7 Hz, 1H), 0.63 (d,J=6.6 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) 6; 199.8, 134.4, 134.1, 129.0,128.6, 77.3, 71.5, 39.7, 24.1, 23.6, 21.1.

[0298] Entry 5a.

[0299] Major diastereomer (less polar isomer):

[0300] t_(r)=12.81 min and 14.26 (major enantiomer) min, % ee (ChiralcelOJ, λ=254 nm, heptane:isopropanol=80:20, 1 mL/min). mp 98° C.[α]D²⁶+23.2 (c 1.42, CHCl₃, 90% ee). IR (KBr) ν cm⁻¹; 3463, 3024, 2952,2856, 1692, 1598, 1578, 1496, 1448, 1398, 1242, 1132. ¹H NMR (300 MHz,CDCl₃) δ; 7.77 (d, J=7.1 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.8Hz, 2H), 7.34-7.18 (m, 5H), 4.99 (dd, J=5.6, 1.7 Hz, 1H), 4.01-3.92 (m,1H), 3.95 (d, J=5.4 Hz, 1H), 2.92-2.74 (m, 2H), 2.18-1.98 (m, 2H), 1.87(d, J=9.8 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ; 200.0, 141.2, 134.0,133.5, 128.8, 128.5, 128.48, 128.40, 126.0, 75.3, 72.1, 35.9, 31.9.Anal. Calcd for C₁₇H₁₈03: C, 75.53; H, 6.71. Found: C, 75.62; H, 6.84.

[0301] Minor diastereomer (more polar isomer):

[0302] t_(r)=10.95 min and 11.91 (major enantiomer) min, (Chiralcel OJ,λ=254 nm, heptane:isopropanol=80:20, 1 mL/min). ¹H NMR (300 MHz, CDCl₃)5; 7.90 (d, J=7.1 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.48 (t, J=7.8 Hz,2H), 7.18-6.98 (m, 5H), 5.22 (dd, J=6.6, 3.7 Hz, 1H), 3.98-3.88 (m, 1H),3.83 (d, J=6.6 Hz, 1H), 2.78 (ddd, J=13.9, 9.3, 4.9 Hz, 1H), 2.52 (ddd,J=13.9, 8.8, 7.8 Hz, 1H), 2.25 (bd, J=9.8 Hz, 1H), 1.78-1.65 (m, 1H),1.45-1.34 (m, 1H). ³C NMR (75 MHz, CDCl₃) δ; 199.6, 141.2, 134.4, 133.9,129.0, 128.6, 128.3, 128.2, 125.8, 76.9, 72.5, 32.4, 31.5.

[0303] Entry 7.

[0304] Major diastereomer (less polar isomer):

[0305] t_(r)=7.73 min (major enantiomer) and 9.33 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=90:10, 1 mL/min). mp 58-59° C. [o]_(D)²⁵−1.6 (c 1.67, CHCl₃, 86% ee). IR (KBr) ν cm⁻¹; 3414, 2920, 2851, 1683,1596, 1578, 1452, 1424, 1316, 1279, 1254, 1101. ¹H NMR (300 MHz, CDCl₃)δ; 7.88 (d, J=7.3 Hz, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.50 (t, J=7.3 Hz,2H), 5.00 (dd, J=5.6, 1.5 Hz, 1H), 3.97 (d, J=5.6 Hz, 1H), 3.96-3.87 (m,1H), 1.96 (d, J=9.5 Hz, 1H), 1.78-1.66 (m, 2H), 1.54-1.22 (m, 10H), 0.88(t, J 6.8 Hz, ¹³H). ¹³C NMR (75 MHz, CDCl₃) δ; 200.3, 134.0, 133.8,128.9, 128.5, 75.5, 72.9, 34.7, 31.8, 29.5, 29.2, 25.9, 22.6, 14.1.Anal. Calcd for C₁₆H2₄O₃: C, 72.69; H, 9.15.

[0306] Found: C, 72.70; H, 9.22.

[0307] Minor diastereomer (more polar isomer):

[0308] t_(r)=13.38 min (major enantiomer) and 14.73 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=95:5, 1 mL/min). ¹H NMR (300 MHz, CDCl₃)δ; 7.95 (d, J=73 Hz, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.51 (t, J=7.3 Hz,2H), 5.23 (dd, J=6.6, 3.7 Hz, 1H), 3.98-3.88 (m, 1H), 3.96-3.87 (m, 1H),3.84 (d, J=6.6 Hz, 1H), 2.26 (d, J=9.8 Hz, 1H), 1.44-1.00 (m, 12H), 0.82(t, J=6.8 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ; 199.8, 134.3, 134.1,129.0, 128.6, 77.0, 73.3, 31.7, 30.8, 29.2, 29.0, 25.4, 22.6, 14.0.

[0309] Entry 8.

[0310] Major diastereomer (less polar isomer): t_(r)=7.64 min (majorenantiomer) and 9.26 min, (Chiralcel OD, λ=254 nm,heptane:isopropanol=90:10, 1 mL/min). mp 62° C. [α]_(D) ²⁵+0.64 (c 2.46,CHCl₃, 87% ee). IR (KBr) ν cm⁻¹; 3462, 3374, 2917, 2849, 1690, 1642,1598, 1582, 1450, 1270, 1116. ¹H NMR (300 MHz, CDCl₃) δ; 7.88 (d, J=7.3Hz, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.50 (t, J=7.3 Hz, 2H), 5.81 (ddt,J=17.1, 10.3, 6.6 Hz, 1H), 5.03-4.90 (m, 3H), 3.96 (d, J=5.9 Hz, 1H),3.95-3.87 (m, 1H), 2.04 (q, J=6.8 Hz, 2H), 1.94 (d, J=9.5 Hz, 1H), 1.70(q, J=7.8 Hz, 2H), 1.55-1.20 (m, 12H). ¹³C NMR (75 MHz, CDCl₃) δ; 200.3,139.1, 133.9, 133.8, 128.9, 128.5, 114.1, 75.4, 72.9, 34.7, 33.7, 29.5,29.4, 29.3, 29.1, 28.9, 25.8. Anal. Calcd for C₁₉H2803: C, 74.96; H,9.27. Found: C, 75.11; H, 9.12.

[0311] Minor diastereomer (more polar isomer):

[0312] t_(r)=13.76 min (major enantiomer) and 14.97 min, (Chiralcel OD,λ=254 nm, heptane:isopropanol=95:5, 1 m/min). ¹H NMR (300 MHz, CDCl₃) δ;7.95 (d, J=7.3 Hz, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.51 (t, J=7.3 Hz, 2H),5.78 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.23 (dd, J=6.6, 3.7 Hz, 1H),5.00-4.87 (m, 2H), 3.98-3.87 (m, 1H), 3.85 (d, J=6.6 Hz, 1H), 2.30 (d,J=9.8 Hz, 1H), 2.00 (q, J=6.9 Hz, 2H), 1.44-1.00 (m, 14H). ¹³C NMR (75MHz, CDCl₃) δ; 199.8, 139.2, 134.3, 134.1, 129.0, 128.6, 114.1, 77.0,73.3, 33.7, 36.7, 29.3, 29.2, 29.0, 28.8, 25.4.

[0313] Entry 9.

[0314] Major diastereomer (less polar isomer):

[0315] t_(r)=13.38 min and 19.47 min, (Chiralcel AD, λ=254 nm,heptane:isopropanol=80:20, 1 mL/min). mp 89° C. [α]_(D) ²⁴-6.8 (c 1.49,CHCl₃, 96% ee). IR (KBr) ν cm⁻¹; 3491, 3374, 3133, 2926, 1855, 1852,1562, 1467, 1384, 1297, 1044. ¹H NMR (300 MHz, CDCl₃); δ 7.61 (d, J=1.7Hz, 1H), 7.32 (d, J=3.7 Hz, 1H), 6.58 (dd, J=3.7, 1.7 Hz, 1H), 4.96 (dd,J=5.6, 0.9 Hz, 1H), 3.83 (d, J=5.6 Hz, 1H), 3.73 (dt, J=8.8 Hz, 1H),2.1-0.93 (m, 12H). ¹³C NMR (75 MHz, CDCl₃) δ; 189.1, 150.3, 146.9,119.0, 112.6, 76.8, 73.7, 41.0, 29.4, 29.2, 26.3, 25.9, 258. Anal. Calcdfor C₁₃H₁₈04: C, 65.53; H, 7.61. Found: C, 65.39H, 7.70.

[0316] Minor diastereomer (more polar isomer):

[0317] t_(r)=9.97 min and 11.46 min, (Chiralcel AD, λ=254 nm,heptane:isopropanol=80:20, 1 mL/min). ¹H NMR (300 MHz, CDCl₃) δ; 7.66(bs, 1H), 7.36 (d, J=3.7 Hz, 1H), 6.60 (dd, J=3.7, 1.7 Hz, 1H), 4.90(dd, J=7.6, 5.4 Hz, 1H), 3.72-3.66 (m, 1H), 3.50 (d, J=7.8 Hz, 1H), 2.21(d, J=83 Hz, 1H), 2.1-0.9 (m, 11H).

[0318] Entry 10.

[0319] Major diastereomer (less polar isomer):

[0320] t_(r)=13.84 min and 16.64 min, (Chiralcel AD, λ=254 rim,heptane:isopropanol=80:20, 1 mL/min). mp 100° C. [α]_(D) ²⁴+25.8 (c1.69, CHCl₃, 95% ee). IR (KBr) ν cm⁻¹; 3414, 3386, 3122, 2903, 1665,1561, 1463, 1388, 1294, 1080, 1031. ¹H NMR (300 MHz, CDCl₃) δ; 7.57 (d,J=1.7 Hz, 1H), 7.33-7.17(m, 6H),6.56(dd, J=3.7, 1.7 Hz, 1H),4.77 (dd,J=5.8, 1.7 Hz, 1H), 4.16-4.06 (m, 1H), 3.82 (d, J=5.8 Hz, 1H), 2.96-2.73(m, 2H), 2.15-1.98 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ; 188.2, 150.2,147.1, 141.4, 128.4, 125.9, 119.3, 112.7, 75.8, 72.0, 35.9, 32.0. Anal.Calcd for C₁₅H₁₆O₄: C, 69.22; H, 6.20. Found: C, 69.40; H, 6.23.

[0321] Minor diastereomer (more polar isomer):

[0322] t_(r)=10.46 min and 11.78 min, (Chiralcel AD, λ=254 nm,heptane:isopropanol=80:20, 1 mL/min). ¹H NMR (300 MHz, CDCl₃) δ; 7.60(d, J=1.7 Hz, 1H), 7.32 (d, J=3.7 Hz, 1H), 7.27-7.06 (m, 5H), 6.57 (dd,J=3.7, 1.7 Hz, 1H), 4.95 (dd, J=6.8, 3.9 Hz, 1H), 4.04 (tt, J=10.3, 3.2Hz, 1H), 3.67 (d, J=6.8 Hz, 1H), 2.83 (ddd, J=13.9, 9.0, 5.1 Hz, 1H),2.61 (ddd, J=13.9, 8.3, 8.0 Hz, 1H), 2.33 (d, J=9.8 Hz, 1H), 1.82-1.47(m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ; 187.7, 150.5, 147.6, 141.4, 128.3,125.8, 119.7, 112.8, 77.0, 72.4, 32.8, 31.6.

Example 19 Preparation of Diol of Known Configuration for Determinationof Absolute Stereochemistries

[0323]

[0324] A solution of the α,β-unsaturated ketone (40 mg, 0.19 mmol) int-butanol (0.5 mL) was added to the mixture of 300 mg of ADmix-α(reagent for Sharpless asymmetric dihydroxylation; see J. Org. Chem.57:2768, 1992; available from ChiRex, Wellesley, Mass.), 50 mg of sodiumbicarbonate, 20 mg of methanesulfonamide in 0.5 mL of t-butanol, and 0.5mL of water. The mixture was stirred at ambient temperature for 15 h.NaHSO₃ was added to the mixture, and it was extracted with ether. Theorganic layer was washed with brine and dried over magnesium sulfate.Evaporation of the solvent under the reduced pressure and purificationof the residue by silica gel column chromatography (PE: ether, 1:1)afforded the diol product (42 mg, 0.181 mmol, 95%, 84% ee). [α]_(D)²⁵+2.5 (c 2.7, CHCl₃).

Example 20 Enantioselective Nitro-Aldol Reactions of Nitromethane(Tables 7-8) Representative Procedure.

[0325] A. Preparation of Catalyst

[0326] Under an argon atmosphere, a solution of diethylzinc (0.36 mL,1.1 M in tol, 0.4 mmol) was added to a stirred and cooled (0° C.)solution of ligand (0.128 g, 0.2 mmol) in THF (2 mL). After the additionthe cold bath was removed and the solution was allowed to stir at roomtemperature for 30 min to make a 0.1 M catalyst solution.

[0327] B. Nitro-Aldol Reaction

[0328] Under an argon atmosphere, a solution of catalyst (0.5 mL, 0.1 Min THF, 0.05 mmol) was added dropwise to a stirred and cooled (−78° C.)suspension of powdered molecular sieves 4A (100 mg, dried at 120° C.under vacuum overnight), aldehyde (1 mmol), and CH₃NO₂ (0.32 mL, 6 mmol)in THF (3 mL). After the addition, the resulting mixture was transferredto a −20° C. cold bath and left to stir for 24 h. The reaction wasquenched by adding aqueous HCl solution (3 mL, 0.5 M), and the resultingmixture was partitioned with Et₂O (10 mL). The organic phase was washedwith water and brine, dried (MgSO₄), and filtered. After the evaporationof the solvent, the residue was purified by silica gel columnchromatography (EtOAc: pet ether, 10:90) to afford the nitro aldolproduct.

[0329] Characterizating Data for Products in Tables 7-8

[0330] All products were purified on silica gel using a EtOAc/pet ethergradient.

[0331] Table 7, all entries.

[0332] [α]²⁵ _(D)+15.87 (c 5.01, CHCl₃) (85% ee); ¹H NMR (300 MHz,CDCl₃) δ 1.0-1.61 (m, 5H), 1.72-1.52 (m, 1H), 1.55-1.85 (5H), 2.58 (brs, 1H), 4.02-4.12 (m, 1H), 4.35-4.50 (m, 2H); ¹³C NMR (75.5 MHz, CDCl₃)δ 25.69, 25.82, 26.02, 27.89, 28.75, 41.37, 42.81, 79.28.

[0333] See Sasai, H. et al., J. Am. Chem. Soc., 1992, 114, 4419.

[0334] Table 8, Entry 1

[0335] [α]²⁵ _(D)+5.44 (c 2.49, CHCl₃) (88% ee); ¹H NMR (300 MHz, CDCl₃)δ 0.97 (d, J=4.4 Hz, 3H), 1.02 (d, J=4.1 Hz, 3H), 1.80 (oct, J=6.8 Hz,1H), 4.1 (ddd, J=5.8, 5.8, 3.2 Hz, 1H), 4.40 (dd, J=13.2, 8.55 Hz, 1H),4.48 (dd, J=13.2, 3.2 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃) δ 17.44, 18.43,31.69, 73.31, 79.23.

[0336] Entry 2

[0337] [α]²⁵ _(D)+29.39 (c 3.39, CH₂Cl₂) (93% ee); ¹H NMR (300 MHz,CDCl₃) δ 0.95 (s, 9H), 2.40 (br s, 1H), 4.04 (d, J=9.77 Hz, 1H), 4.37(dd, J=12.9, 10.0 Hz, 1H), 4.52 (dd, J=12.9, 2.2 Hz, 1H); ¹³C NMR (75.5MHz, CDCl₃) δ 25.58, 34.27, 76.14, 78.19.

[0338] Entry 3

[0339] [α]²⁵ _(D)+16.32 (c 2.10, CH₂Cl₂) (92% ee); FTIR (film) 3442,1554, 1463, 1383 cm; ¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.32, 6H),1.20-1.56 (m, 5H), 2.38 (d, J=4.6 Hz, 1H), 4.32-4.42 (m, 1H), 4.43 (s,1H), 4.46 (d, J=2.2 Hz, 1H); ¹³C NMR (75.5 MHz, CDCl₃) δ 6.60, 6.68,16.51, 17.03, 39.91, 65.37, 74.65.

[0340] Entry 4

[0341] [α]²⁵ _(D) −2.17 (c 1.95, CH₂Cl₂) (87% ee); FTIR (film) 3442,2960, 1555, 1469, 1385 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.95 (d, J=4.4Hz, 3H), 0.97 (d, J=4.4 Hz, 3H), 1.16-1.30 (m, 1H), 1.44-1.56 (m, 1H),1.76-1.90 (m, 1H), 2.48 (d, J=2.7 Hz, 1H), 4.32-4.44 (m, 3H);); ¹³C NMR(75.5 MHz, CDCl₃) δ 21.73, 23.17, 24.29, 42.39, 66.92, 80.93.

[0342] Entries 5a-b

[0343] [α]²⁵ _(d) −13.56 (c1.32, CH₂Cl₂) (85% ee); ¹H NMR (300 MHz,CDCl₃) δ 1.72-1.94 (m, 2H), 2.64 (br s, 1H), 2.20-2.92 (m, 2H),4.26-4.35 (m, 1H), 4.39 (d, J=1.9 Hz, 1H), 4.41 (s, 1H), 7.18-7.38 (m,5H); ¹³C NMR (75.5 MHz, CDCl₃) δ 31.29, 35.06, 67.69, 80.49, 126.31,128.40, 128.62, 140.55; mp 87° C.

[0344] Entry 6

[0345] [α]²⁵ _(D)+0.52 (c 0.59, CH₂Cl₂) (86% ee); FTIR (film) 3432,2930, 1556 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.85 (q, J=11.2, 6.1 Hz, 2H),3.34 (d, J=3.7 Hz, 1H), 3.64-3.76 (m, 2H), 4.44 (dd, J=17.1, 6.8 Hz,2H), 4.44-4.60 (m, 1H), 4.53 (s, 2H), 7.21-7.43 (m, 5H); ¹³C NMR (125.6MHz, CDCl₃)δ 33.22, 67.26, 67.94, 73.46, 80.38, 127.74, 127.98, 128.56,137.42. Anal. Calcd for C₁₁H₁₅NO₄: C. 58.66; H, 6.71.

[0346] Entry 7

[0347] [α]²⁵ _(D)−1.03 (c 1.70, CH₂Cl₂) (19:1 dr); FTIR (film) 3441,2922, 1555, 1452; 1381 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.98 (d, J=6.6Hz, 3H), 1.16-1.50 (m, 4H), 1.60 (ddd, J=10.2, 3.4, 3.4 Hz, 1H), 1.62(s, 3H), 1.71 (s, 3H), 1.72-1.80 (m, 1H), 1.94-2.09 (m, 2H), 2.46 (dd,J=4.6, 1.46 Hz, 1H), 4.36-4.48 (m, 3H), 5.08-5.14 (m, 1H); ¹³C NMR(125.6 MHz, CDCl₃) δ 17.93, 19.13, 25.59, 25.96, 28.71, 37.79, 40.83,66.85, 81.34, 124.50, 131.91. Anal. Calcd for C₁₁H₂₁NO₃: C. 61.37; H,9.83.

[0348] Entry 8

[0349] [α]²⁵ _(D)+33.02 (c 3.71, CH₂Cl₂) (91% ee); ¹H NMR (300 MHz,CDCl₃) δ 2.80 (br s, 1H), 4.52 (dd, J=13.4, 3.2 Hz, 1H), 4.62 (dd,J=13.4, 9.3, 1H), 5.48 (dd, J=7.31, 3.21H), 7.32-7.50 (m, 5H); ¹³C NMR(125.6 MHz, CDCl₃) δ 70.98, 81.19, 125.92, 128.98, 129.03, 138.26.

[0350] Entry 9

[0351] [α]²⁵ _(D)+17.67 (c 2.41, CH₂Cl₂) (93% ee), FTIR (film) 3541,1552, 1418, 1378 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 2.80 (br s, 1H), 4.62(dd, J=14.2, 10.2 Hz, 2H), 6.22 (dd, J=9.0, 3.2 Hz, 1H), 7.44-7.56 (m,3H), 7.72 (d, J=7.1 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.84 (d, J=8.1 Hz,1H), 7.99 (d, J=8.6 Hz, 1H); ¹³C NMR (125.6 MHz, CDCl₃) δ 68.30, 80.77,121.79, 123.86, 125.51, 126.10, 127.09, 129.32, 129.43, 129.53, 133.50,133.73.

[0352] Entry 10

[0353] [α]²⁵ _(D)+26.79 (c 2.02, CH₂Cl₂) (78% ee), FTIR (film) 3489,2939, 2839, 1608, 1552, 1517, 1465, 1379 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ3.87 (s, 3H), 3.89 (s, 3H), 4.48 (dd, J=13.2, 3.2 Hz, 1H), 4.61 (dd,J=13.2, 9.5 Hz, 1H), 5.40 (dd, J=9.5, 2.9 Hz, 1 H), 6.83-6.95 (m, 3H);¹³C NMR (125.6 MHz, CDCl₃) δ 55.92, 55.93, 70.85, 81.29, 108.73, 111.22,118.31, 130.59, 149.38.

[0354] Entry 11

[0355] [α]²⁵ _(D) 5.87 (c 1.26, CH₂Cl₂) (92% ee); FTIR (film): 3518,2982, 1736, 1557, 1341, 1131 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 1.60 (s,9H), 4.18 (d, J=7.1 Hz, 1H), 4.84-4.68 (m, 2H), 5.72-5.65 (m, 1H), 6.12(t, J=3.4, 1H), 7.19 (dd, J 3.4, 1.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ27.9, 64.9, 78.8, 85.5, 110.6, 113.1, 122.9, 131.8, 150.0 cm⁻¹.

Example 21 Preparation of Mandelic Acid Derivative for Determination ofAbsolute

[0356]

[0357] The nitroaldol adduct of nitromethane with 3-phenylpropionaldehyde (Table 8, entries 5a-b) (0.1 g, 0.51 mmol) was stirredin the presence of 10% Pd/C (20 mg) in MeOH (2.5 mL) under H₂ atmosphere(1 atm) for 3 h. The mixture was then filtered through a pad of celite,using MeOH as wash, and the solvent was evaporated. The crude amine wasre-dissolved in CH₂Cl₂ (5 mL) and i-Pr₂NEt (0.18 mL, 1.02 mmol), and(BOC)20 (0.123 g, 0.563 mmol) was subsequently introduced into thereaction solution. After the mixture was allowed to stir for 3 b at rt,it was diluted with EtOAc and washed with sat. NH₄Cl solution, water,and brine, dried (MgSO₄), and concentrated. The residue was purifiedover silica gel chromatography column using 10% EtOAc/pet ether to givea clear oil (0. 104 g, 77%): [α]²⁵ _(D) −8.86 (c 0.56, CH₂Cl₂), FTIR(film) 3446, 2955, 1703, 1510, 1265 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.46(s, 9H), 1.79 (q, J=7.5 Hz, 2H), 2.72 (ddd, J=13.9, 8.1, 8.1 Hz, 1H),2.83 (ddd, J=13.4, 8.1, 8.1 Hz, 1H), 3.06-3.14 (m, 1H), 3.32 (br d,J=14.2 Hz, 1H), 3.70-3.77 (m, 1H), 4.95 (br s, 1H), 7.20-724 (m, 3H),7.28-7.32 (m, 2H); ¹³C NMR (125.6 MHz, CDCl₃) δ 28.35, 31.80, 36.37,46.70, 71.06, 79.71, 125.92, 128.39, 128.43, 141.71.

[0358] EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; 59 mg, 0.307mmol) was added to a stirred solution of the protected amine, above (51mg, 0. 192 mmol), (S)-(+)-α-methoxy phenylacetic acid (48 mg, 0.288mmol), and DMAP (2 mg, 0.019 mmol) in CH₂Cl₂ (3 mL). The solution wasallowed to stir for Sh at rt, and it was then diluted with Et₂O (20 mL)and washed with 0.5 N HCl, saturated NaHCO₃ solution, and brine. Theorganic phase was dried (MgSO₄) and concentrated to give the methoxyester product as a clear oil: [α]²⁵ _(D)+41.72 (c 4.30, CH₂Cl₂); FTIR(film) 3435, 3061, 2979, 1749, 1713, 1606, 1508, 1266, 1171 cm⁻¹; ¹HNMR(500 MHz, CDCl₃)δ 1.41, 1.81-1.96(m, 2H), 2.62 (t, J=8.1 Hz, 2H), 3.02(ddd, J=14.2, 14.2, 6.9 Hz, 1H), 3.30 (ddd, J=17.8, 6.3, 3.4 Hz, 1H),3.44 (s, 3H), 4.02 (br s, 1H), 5.03 (dddd, J=8.0, 7.5, 7.5, 4.9 Hz, 1H),7.10-7.50 (m, 10H); ¹³C NMR (125.6 MHz, CDCl₃) δ 28.57, 31.68, 33.44,43.76, 57.57, 74.24, 79.65, 82.70, 126.30, 127.32, 128.56, 128.70,129.11, 129.24, 136.78, 141.28, 155.92, 170.59.

Example 22 Conversion of Nitroaldol Product into Chiral α-HydroxyCarboxylic Ester

[0359]

[0360] NaNO₂ (0.18 g, 2.61 mmol) was added in one portion to a stirredsolution of the nitroaldol adduct of nitromethane with 3-phenylpropionaldehyde (Table 8, entries 5a-b) (0.17 g, 0.871 mmol, 84% ee) inAcOH (0.54 mL, 8.71 mmol) and DMSO (2 mL). The resulting solution wasstirred overnight at rt and for 3 h at 35° C. The reaction was quenchedwith 0.5 HCl (5 mL) and extracted with CH₂Cl₂ (5 mL×4) and EtOAc (2mL×2). The combined organic phases were dried (Na₂SO₄) and the residuewas purified over silica gel using 50% EtOAc/pet ether to give thecarboxylic acid. This product was redissolved in Et₂O and treated withTMSCHN₂ to give the ester (0.11 g, 69%) as an oil: [α]²⁵ _(D)+29.5 (c1.02, CH₂Cl₂) (85% ee), tr=10.88 (major) and 17.12 min (Chiralcel AD,λ=254 nm, heptane:isopropanol 95:5, 0.95 ml/min).

[0361] While the invention has been described with reference to specificmethods and embodiments, it will be appreciated that variousmodifications may be made without departing from the invention.

It is Claimed:
 1. A method of conducting an enantioselective aldolreaction between an aldehyde and a donor molecule selected from a ketonebearing an a-hydrogen and a nitroalkyl compound, the method comprisingcontacting said aldehyde and said donor molecule in the presence of acatalytic amount of an asymmetric catalyst, wherein said catalyst is acomplex of a Group 2A or Group 2B metal with a chiral ligand of formulaI:

where R¹-R⁴ are aryl groups, which may be the same or different, each ofwhich is unsubstituted or substituted with one or more substituents X,where each X is independently selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- oraryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen, whereinR¹ and R², or R³ and R⁴, or both of these combinations, may be linked atan α-carbon of each said group to form a tricyclic or larger ringsystem; m is an integer from 0 to 3; each of R⁵ and R⁶ represents one ormore substituents independently selected from the group consisting ofhydrogen and X as defined above; and R⁷ represents one or moresubstituents on the phenol ring independently selected from the groupconsisting of hydrogen, X as defined above, and a further fused ring;under conditions effective to produce an aldol reaction product which isenriched in one of the possible stereoisomeric products of suchreaction.
 2. The method of claim 1, wherein the Group 2A or Group 2Bmetal is selected from the group consisting of Zn, Cd, Mg, Ca, and Ba.3. The method of claim 1, wherein the metal is Zn.
 4. The method ofclaim 1, wherein each of R¹-R⁴ is selected from phenyl, α-naphthyl, andβ-naphthyl, unsubstituted or substituted with a group selected from X asdefined in claim
 1. 5. The method of claim 4, wherein each of R¹-R⁴ isselected from phenyl, α-naphthyl, and β-naphthyl, unsubstituted orsubstituted with a group selected from lower alkyl, lower alkoxy, andhalogen.
 6. The method of claim 1, wherein m is
 1. 7. The method ofclaim 6, wherein each of R and R is hydrogen.
 8. The method of claim 1,wherein each Re is independently selected from hydrogen, lower alkyl,lower alkoxy, and halogen.
 9. The method of claim 1, wherein the ketoneis an aryl methyl ketone or an aryl (hydroxymethyl) ketone.
 10. Themethod of claim 1, wherein the donor compound and aldehyde are presentin a molar ratio between about 1:1 and 10:1.
 11. The method of claim 1,wherein the amount of catalyst is about 2.5 to 10 mole percent, relativeto moles of aldehyde.
 12. A catalytic composition consisting of acomplex of a Group 2A or Group 2B metal with a chiral ligand of formulaI

where R¹-R⁴ are aryl groups, which may be the same or different, each ofwhich is unsubstituted or substituted with one or more substituents X,where each X is independently selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- oraryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen, whereinR¹ and R², or R³ and R⁴, or both of these combinations, may be linked atan α-carbon of each said group to form a tricyclic or larger ringsystem; m is an integer from 0 to 3; each of R⁵ and R⁶ represents one ormore substituents independently selected from the group consisting ofhydrogen and X as defined above; and R⁷ represents one or moresubstituents on the phenol ring independently selected from the groupconsisting of hydrogen, X as defined above, and a further fused ring.13. The composition of claim 12, wherein the Group 2A or Group 2B metalis selected from the group consisting of Zn, Cd, Mg, Ca, and Ba.
 14. Thecomposition of claim 13, wherein the metal is Zn.
 15. The composition ofclaim 12, wherein each of R¹-R⁴ is phenyl, a-naphthyl, or β-naphthyl,unsubstituted or substituted with a group selected from X as defined inclaim
 12. 16. The composition of claim 15, wherein each of R¹-R⁴ isphenyl, α-naphthyl, or P-naphthyl, unsubstituted or substituted with agroup selected from lower alkyl, lower alkoxy, and halogen.
 17. Thecomposition of claim 12, wherein m is
 1. 18. The composition of claim17, wherein each of R⁵ and R⁶ is hydrogen.
 19. The composition of claim12, wherein each R⁷ is independentyl selected from hydrogen, loweralkyl, lower alkoxy, and halogen.
 20. The composition of claim 12,wherein said chiral ligand is selected from the group consisting ofligands 1a-1n as disclosed herein.
 21. The composition of claim 20,wherein said chiral ligand is selected from the group consisting ofligands 1a, 1c-d, and 1 m as disclosed herein.
 22. A catalyticcomposition formed by contacting a chiral ligand of formula I:

where R¹-R⁴ are aryl groups, which may be the same or different, each ofwhich is unsubstituted or substituted with one or more substituents X,where each X is independently selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- oraryl sulfonyl, sulfonamide, amine, hydroxy, cyano, nitro, and halogen,wherein R¹ and R², or R³ and R⁴, or both of these combinations, may belinked at an α-carbon of each said group to form a tricyclic or largerring system; m is an integer from 0 to 3; each of R⁵ and R⁶ representsone or more substituents independently selected from the groupconsisting of hydrogen and X as defined above; and R⁷ represents one ormore substituents on the phenol ring independently selected from thegroup consisting of hydrogen, X as defined above, and a further fusedring; with a Group 2A or Group 2B metal compound which is capable ofgenerating a metal alkoxide upon reaction with an alcohol.
 23. Thecomposition of claim 22, wherein said Group 2A or Group 2B metalcompound is a dialkyl metal, dialkoxy metal, alkyl metal halide, alkyl(dialkylamino) metal or alkyl (diarylamino) metal.
 24. The compositionof claim 22, wherein the Group 2A or Group 2B metal is selected from thegroup consisting of Zn, Cd, Mg, Ca, and Ba.
 25. The composition of claim24, wherein the metal is Zn.
 26. The composition of claim 25, whereinsaid metal compound is a di(lower alkyl) zinc compound.
 27. Thecomposition of claim 22, wherein each of R¹-R⁴ is phenyl, a-naphthyl, orβ-naphthyl, unsubstituted or substituted with a group selected from X asdefined in claim
 22. 28. The composition of claim 22, wherein each ofR¹-R⁴ is phenyl, a-naphthyl, or β-naphthyl, unsubstituted or substitutedwith a group selected from lower alkyl, lower alkoxy, and halogen. 29.The composition of claim 22, wherein m is
 1. 30. The composition ofclaim 29, wherein each of R⁵ and R⁶ is hydrogen.
 31. The composition ofclaim 22, wherein each R⁷ is independentyl selected from hydrogen, loweralkyl, lower alkoxy, and halogen.
 32. The composition of claim 22,wherein said chiral ligand is selected from the group consisting ofligands 1a-1n as disclosed herein
 33. The composition of claim 32,wherein said chiral ligand is selected from the group consisting ofligands 1a, 1c-d, and 1 m as disclosed herein.
 34. A chiral ligand offormula I:

where R¹-R⁴ are aryl groups, which may be the same or different, each ofwhich is unsubstituted or substituted with one or more substituents X,where each X is independently selected from alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, aralkynyl, alkoxy, aryloxy, amide, alkyl- oraryl sulfonyl, sulfonamide, hydroxy, cyano, nitro, and halogen, whereinR¹ and R², or R³ and R⁴, or both of these combinations, may be linked atan α-carbon of each said group to form a tricyclic or larger ringsystem; m is an integer from 0 to 3; each of R⁵ and R⁶ represents one ormore substituents independently selected from the group consisting ofhydrogen and X as defined above; and R⁷ represents one or moresubstituents on the phenol ring independently selected from the groupconsisting of hydrogen, X as defined above, and a further fused ring.35. The ligand of claim 34, wherein each of R¹-R⁴ is phenyl x-naphthyl,or naphthyl, unsubstituted or substituted with a group selected from Xas defined in claim
 34. 36. The ligand of claim 35, wherein each ofR¹-R⁴ is phenyl α-naphthyl, or naphthyl, unsubstituted or substitutedwith a group selected from lower alkyl, lower alkoxy, and halogen. 37.The ligand of claim 34, wherein m is
 1. 38. The ligand of claim 37,wherein each of R⁵ and R⁶ is hydrogen.
 39. The ligand of claim 34,wherein each R⁷ is independentyl selected from hydrogen, lower alkyl,lower alkoxy, and halogen.
 40. The ligand of claim 34, selected from thegroup consisting of ligands 1a-1n as disclosed herein.
 41. The ligand ofclaim 40, selected from the group consisting of ligands 1a, 1c-d, and 1mas disclosed herein.